All right. So well, good morning everyone. Thank you for coming to my, to my now, now pre recorded talk just to be like everyone else I'm using an electronic prophylaxis. But yeah, so, so strategies for ab initio biomolecular force field development this whole idea of ab initio force fields has been very attractive for at least 15 years or so ever since essentially we had, we had the compute capacity to do the quantum calculations that would describe any of these molecules that we're interested in. And so in the last, in the last five to 10 years, we've really started to see a raise hope in this direction. So I want to start just by reviewing the differences between the small molecule force field, which a lot of the other talks have covered in I think great detail and I've been I've been watching very, very impressed with a lot of the work that's being done in open force field, the small molecule force fields versus the bottom molecular force fields and you can see these differences manifest themselves even in the way they even in not just the fitting strategies but even in the way people talk about their force fields and then it becomes an issue okay well how do we pair the small molecule force field or even like the third category of force fields or major category that I'm not mentioning here is water models. In fact, but you know people talk about pairing the bottom molecular force field model or pairing small molecule force field to the bottom molecular force field I think we just have to look at details on the goals of what they're what they're trying to model at first. So with the small molecule force field you want to capture a space of trillions or thousands of trillions of potential molecules chemical space with the bottom molecular force field you have a much more limited palette. You can go up to 100 common monomers because you think about 20 amino acids in nature and then some modifications of those amino acids phosphorylation and such.  So we're talking really about a palette of up to 100 or maybe 200 individual residues in a bio molecular force field. With the chemistry and the small molecule force field you have potentially a lot of nasty chemistry you can have some toxicity, but you can have things that take a lot of energy to synthesize. And in biology, you could have things like you can you can have things like the penicillin and some of these lactum range that are pretty highly strained, but really you're not going to see quite the chemical diversity in that and and and the common theme being of course that these things are products of metabolism they're also going to be recycled and broken down by metabolism. So there is a there's a palette of chemical bonds and ways to connect these things and of course the the ATP driven processes that can create these things there's a there's a limited energy budget for making them. So then the key properties for the small molecule force will become things like hydration free energy as you want, you want binding free energies we want to know what the equilibrium constant is going to be for this for this drug binding or for this, or even like the the properties of this neat liquid. We'd like to know how you know, not just benzene or some benzene derivative is going to be solubilized in CO2. Then the biomolecular force field we want structure, primarily we want secondary and tertiary structures of polymers we want to see how hydrogen bonding particularly dictates the secondary structure and then how weaker interactions dictate the interactions of the secondary structures to fold into protein or an RNA enzyme. This all translates into the ways we train these force fields so the parameter libraries and interpolation strategies that I think open FF is doing very well to explore and to and to hone for the small molecule force fields. You see sort of an analog in the ways to to perhaps have libraries and we can start to think about, you know, bond order corrections and things for bottom molecular force fields but largely the bottom molecular force fields because they are so sensitive to small perturbations and we were seeing small perturbations create large differences and tertiary structures whether your protein folds or not. The bottom molecular force fields the strategy tends to be improve on something that already works modify only a few parameters of it and throw lots of graduate students at the problem. So then the validation strategies being for the small molecule force field validation is still the bulk of the work generating the fitting data and doing the fitting is important but the validation is for either of these categories is quite lengthy. The fleets of TI or alchemical binding free energy calculations getting back to the goals of the model for for the small molecules and then for the bottom molecular force field you're looking at microsecond time scale simulations. And then the latest amber force field and I'll talk about a little bit amber FF 19 as the that was validated using five microseconds so 5000 five milliseconds 5000 microseconds of combined replica exchange simulations on various healer sees to try and get those to get the properties right. But then you can see things other other things on the micro second time scale enzyme binding that can occur there but mostly you're looking at NMR terms and NMR relaxation constants. And so by molecular force fields in this sense they've been pretty successful at replicating a lot of these things again on the micro second time scale and we're now in a regime where on the micro second time scale we can start to see these binding events these drug ligand interactions that are relevant to biology so in some sense the computation is ready now to to have both force fields working in conjunction in concert and now it comes a question can we can we align the ways that we make both of these models. So a brief history of the amber protein force fields this is sort of my stomping grounds. The protein force fields are a vaunted a very respected class of the Obama like our models, particularly the protein force fields. It started in 1995 back in the Lake Peter Coleman's lab with Wendy Cornell you had Kenny Burr as you had Chris Bailey, all in that crowd. So they developed the harm 94 set along with the what's been called the Cornell charge set so FF 95 incorporated harm 94 which is the bonnet parameters. And then the Cornell charge set was all based on 631 G star Hartree Fock calculations which nowadays they they take minutes if not seconds on a on a modern computer. It was pretty significant back in 1994 of course. And that that charge set because it has some propensity towards polarization in certain chemical groups that actually performed very well and it's, and it is still in use today in fact even in FF 19 SB so 24 years later they're still using the same charge set. So here on this slide is trying to indicate, you know, as, as seen in the legend here. If you have a new charge model then you did a torsion refit maybe you did some Leonard Jones refit so June may Wang, who's still with the amber amber group and the consortium. He started in the late 90s working on a derivative of FF 95 became FF 99. It really took off when Victor Hornak came in so the hydrogens. Particularly the hydrogen Leonard Jones parameters got diversified by June May. But then Victor Hornak came in and along with people like Robert Abel and Carlos Sarling's group. And it was also involved in this effort but this this thing in 2006 the next torsion refit when we started to incorporate more mp2 level calculations. This became FF 99 SB and this 99 SB has been a, it was a very long lived and very successful protein force field but really you have to recognize that it was a limited refit of what was already in FF 95. It got to as far as 2014 before James Meyer also in Carlos summer group came along and did some additional torsion refits. They got even better reproduction of publicity and perhaps beta sheet propensity still using the same charge that of course around 2014 2016 we had sort of a flowering of different different force field so I got in there and I made a complete refit of different charge set all new torsion parameters and my own some of my own Leonard Jones edits. That first one actually didn't work very well but a student of Lillian Chung's came along and I was able to work with him I'll talk more about this in detail but in 2015. We came out with what's called now FF 15 IPQ so successor to 14 IPQ but in fact a complete refit of everything. And this one got basically backtracked a lot of the Leonard Jones refitting, but it got the salt bridge propensity is correct which 14 IPQ really was the Achilles heel. And so 15 IPQ and 14 SP they they are very much neck and neck they're both very, very good force fields and our only Ping Wang in the open force field consortium came out around the same time so there were essentially three very good amber force fields. Ping made a complete torsion refit not a limited torsion refit but a complete one of all the side chains and all the protein parameters, but again, still keeping the Cornell charts that so I sort of put him as as a branch in that original line, whereas Ping Wang force field which has since been modified by Robert Best and later D Shaw group, and then the IPQ line of force fields over here on the very right, which I kind of started and Carl DeBec really did an excellent job on and since I've just been involved in writing a manuscript for Anthony Bogey so Italian cars, and perhaps Italian force fields we're going to say they're very well made, but Anthony Bogey and another student with William Chong they've made another 900 parameters torsions and new charge parameters for unnatural amino acids. So I'm really actually very pleased with their success. I helped them through generating about the first 30 of those parameters but I'm very pleased that I didn't hear back from them thinking that maybe they dropped the project and all of a sudden no in fact they finished it. They didn't need my help. So they needed my program but not my help and I was very happy about that. But there so there there's a quite a crop of force fields within the amber community, and it's remarkable how long lived one of the chart sets is, but we still have many options for many different ways we can go. And so the thing I'm going to talk about is the branch that I started back in 2013 2014 so this I pull Q the IPQ line of force fields. This idea started with Cameron's honest and it goes all the way back to something in the around 2000 or so. From some work by phone in stone, but Cameron's honest took a look at a set of dipoles and or just imagine the theoretical set of dipoles. That's in a in an electrostatic field strong enough or or generated by things that are large enough. It's basically like in a temperature control bath, but this is an electrostatic field that the charges do not reciprocally influence. And if you look at the way those charges if they're inducible dipoles if you allow them to polarize to equilibrium. And then you look at the energy of that system you realize, ah, in fact, what you have is is the energy of a system of fixed dipoles as if you had just taken the configuration of the polarized dipoles neglected the fact that it took energy to polarize them. And then average that with the energy of the dipoles in vacuum phase. So transitioning to the monopole systems we've got. In fact, the argument became what we should do is compute the polarized charge distribution neglect the fact for the moment that the energy of polarizing is not trivial. And then average that polarized charge distribution with the vacuum phase charge distribution for the same molecule and same configuration. And thereby account for the polarization energy difference in the fact that the charges of our fixed charge model did not polarize to the full extent that they would in the polarized model simply because we have to account for that energy in some fashion. And this idea is one that's sort of gained a lot of traction in various circles other people have made edits to the article Q force fields, but particularly the the open force field team has has taken this a little bit further, making it a sliding scale how much do we mix the polarized and the the unpolarized the vacuum phase charge sets how much do we mix them and the mixing parameters they come up with around point four to point six and leaning in fact towards the the polarized charge distribution. Which I'm not going to talk about too much more but which seems to be easier to fit electrostatic potential fits of a polarized charge distribution, although it sounds like it would be stronger are in fact easier to do with point charges nuclear centered models and the vacuum phase charge distribution. So you might have been seeing in that last slide there was sort of a cyclical process and indeed it was it was an iterate to convergence sort of thing because with the polarized charge distribution. If you polarized the the charge in the molecule what we were doing is we were getting a bath of solvent molecules and doing and dissimulations to to get an average equilibrium solvent charge density and then use that in the quantum calculation and the q m m m sense to to induce the molecule to polarize and then measure you know what would the polarized charge distribution come out to be. Well, if you change the initial charge distribution in your molecular mechanics model then the solid charge distribution is going to change a little bit and you have to do that iterate to convergence. Similarly with the the torsion fitting. What we were doing is looking at well there's there's a lot of different parameters here to fit. As we, you know, as we do more and more of this, the generational learning in this case that we were doing was, let's make a molecular mechanics model that perfectly or as close as possible mimics the quantum mechanical energy surface. Over the configuration space that that molecular mechanics model is going to explore in a simulation. So we would fit a force field, and then we would do molecular mechanics optimizations to those same configurations and then recalculate q m energies for those re optimized configuration and see okay did our model learn correctly did it actually track the q m surface as it as we allowed it to drive the molecular configuration into a new state. And by doing that so we had another sort of the generational learning a cyclical process. And we were doing this all in conjunction with the ipel q protocol. And by the first time I had, I had done a torsion fit for this new polarized charge center this semi polarized charge that I realized, okay, we have all this gas phase quantum data. But we have polarized charges and the polarized charges the internal electrostatic energy is a part of the energy surface so what do we do. And the answer that I came up with which sort of really started the ipel q line was that okay, we do have to charge sets we have to look at them individually even though we're going to combine them. We have to say okay take the gas phase charges and use those during the torsion fitting we're going to fit torsion parameters in the context of those gas phase charges using gas phase quantum data. And then we're going to transfer those those torsion parameters to work in concert with the polarized charge set. And do our simulations. And so that, you know, wheels within wheels sort of validation process roll forward. And the first thing that came out was ff 14 ipq. As you can see in this timeline here. It was all this is all least squares torsion fitting is least squares electrostatic potential fitting so it's it's a one off you you fit the you you fit the force field but then you have to let the force field drive the molecule and see where it's going to take things. And then make new fitting data and that's where again the cyclical process is coming from. So we, we went through a lot of the formalities of how we do the, the ipel q line. And I made a sort of a disastrous mistake with refitting some of the winter Jones in too harsh a manner, but Carl WX is the one who caught this so after in 2014 publishing 14 ipq. He called me up and said, you know, I think I think there's something wrong and I said, I think you're right I've been seeing a lot of stickiness like sidechain sticking to backbones and things starting down for where they shouldn't. And he said, Well, I think I know what's wrong. And I said, I think you're right. So what we did was we rolled back a lot of the Leonard Jones refitting and we put it all instead on the polar hydrogens. We got a preliminary 15 IPQ and we had all this infrastructure in place so in only three months or so, we were able to go down here and incorporate a lot of new torsions, lots and lots of new data we had nearly a quarter million data points, single point calculations on various dipeptide tripeptide residues. And then we had three months later we had our finalized 15 IPQ for still which, like I said is, you know, it's very competitive in terms of its performance but there's a very there's also a very high bar to meet in terms of the way molecular force fields for proteins behave these days. So one thing that we did along along the way was to incorporate this these angle refinements so we weren't just working with torsion refinements anymore we're also at least squares optimization of the angles. And again this is all done in one big matrix fitting the angles and the torsions are all fitted simultaneously. It really does appear that the angle of refitting did did a lot of good for not just the secondary structure stability but also things like these alanine five j coupling so this is really looking at. It's looking at backbone propensity things that will sort of evolve into secondary structure as you get from a five mer to a 10 mer and a 15 mer things like that. But 15 IPQ was one of the first force fields to get below one mean high squared value in any of these by any of these metrics these cardless coefficients depending on which set you choose, you may or may not get different answers. But the 15 IPQ force field did extremely well by several of these metrics in in getting the getting these j couplings covered. And just in case anyone's wondering well how did you fit the angles we were fitting both equilibria as well as the stiffness constant the stiffness constant spending those things it's it's pretty obvious because it's just like putting a torsion amplitude. But in order to fit the equilibrium so we're we're not saying the angle has got to be 109 it could be 104 114 least squares to configure that out. And the way that works is there's two parabolas two basis functions, the sum of two parabolas is another parabola. And okay you can see that the black here the black line the minimum, the value of the minimum actually changed while the position the minimum change but the overall height of the minimum changed the steepness of the parabola is is a consequence that we're fitting. But in order to account for the fact that the value of the tide changed for these models, we have one additional constant, essentially per system that it can that pretty much obviates all of that so all of this is being taken care of we just have two basis functions and we are fitting with complete mathematical rigor the equilibrium value as well as the stiffness of these angles. And so then we can look at things like alpha helical propensity and K-19 we'll look at alpha helical propensity in the FF-19 SB force field as well. The only thing I can say here that's, you know, particularly successful it's a little bit shy of the 40% target we want these things in fact to be metastable. And in fact we do see the helix unfolding and then refolding at various times in the simulation. I still think that you know that the overall propensity maybe even less than we measured we did throughout first microsecond of these runs in order to measure it but it's it's it's very difficult to look at these things and think okay, we do need enhanced sampling and probably even something on the tens of microseconds time scale for each of these temperatures to really understand exactly what's going on here. And in the later slide I'll show you that for FF-19 SB that is what they did. Beta sheet propensity again you know we're getting beta sheets folding and unfolding this thing is supposed to be about 50% folded at 295 Kelvin. I think it's again a little bit shy but it's it's ballpark, you know, and we do see transient stability of this thing so this is this is actually all very very good news especially considering we've completely refitted the charge set. We've completely refitted the torsion set and some of the angle parameters as well so this is this is different force field this is completely sui generis. And finally I'm just going to review a trip cage folding we got with this thing we we did get about the right melting temperature for trip cage it's about it's supposed to melt around 300, 305. And we see it you know this about what we see happening for FF-14 SB the contemporary to 15 IPQ. They also got about 305 to 310 melting temperatures so again these are both the force fields derived by very different parameters of all different parameters, perhaps it's safe for a few of the bonded parameters and some of the heavy out of Leonard Jones, but they're very very different force fields they get very similar results. And we can ask a question so if we run on the way back here and look at this so right I've got polarized charge set I've got a gas phase charge set and I did this funny thing of fitting the torsions and the conjunct you know in concert in the context of the gas phase charges, I'm just going to combine them with polarized charges to actually do simulations. Well, what if I just run with the gas phase charges because everyone tends to take a charge set and then fit torsions in the context of that charge and then roll. Well, if I had done that in fact we did this study. We did trip cage as well as a number of other, just repeating the validation that we've done for 15 IPQ and a follow up. And if we take just the vacuum phase charges the yellow line that you see here trip cages melting way too early. In fact, it's already melting at 285 kelvin I'm sorry I don't have the temperatures on these plots but the one in the upper left here again is 275. And so then 285 it's still melting 295 we didn't see a melting event but it looks like at the very end here we might have one of might have started and then for all the other temperatures it melts. So what if we had done, which is essentially the 14 SB fitting protocol take the polarized charges fit torsions in the context of the polarized charges with gas phase data and run simulations. If we have done that things actually do look better. But if we have just followed that protocol strictly and again making an ab initio force field that way without any intervention without, you know, again many graduate students looking over the thing and making sure we still got some problems. Okay, so the 15 IPQ to solve that is a fake force field made with what I think is the wrong protocol it turned out to be slightly worse than the canonical protocol that we that we put forward.  And so, you know, we can, there was this and there was some little less stability in a GB three protein it's a small globular protein, but from what from this what we can say is that the way we made 15 IPQ using the polarized charge set in simulations but training torsion and bonded parameters with the backing phase charge set. That was the best option of the these three. You know, certainly you need a polarized charge set that's that's a given from from this and other data we collected. So having the polarized charge set seems to be, no matter how you did the torsions seems to be the bulk of the of the battle there, you know, once you've got that polarized charge set the way you fitted the torsions. There is some consequence to it but in fact just having the charges be polarized ensures a lot of tertiary structure is maintained in these simulations. And I do want to not just to my own warrant for for this entire talk but I want to mention some of the latest work that's been done in the similar group which is this very impressive FF 19 SB force field. This is a CMAP based force field I'm going to talk more about CMAPs a little bit later, but they did the CMAP fitting and I have to commend them for for how they did it or for the effort they put into doing it. And the ambition they had because essentially they had 9000 parameters and they came out with a force field that doesn't appear to be too overfitted. So this is I think this is a very good thing Carlos is quite circumspect when he talks about this saying well we think it's better than 14 SB I think he's correct. I think you know this this is a very again a very solid product from the similar group. And from this slide here this is helical propensity this slide represents 5000 microseconds so five milliseconds of MD across about 80 different simulations or 80 different systems each amino acid, a helix of each amino acid. And with these four different force field combinations. So the OPC water model is a four point water it's, it's a funny looking water model but in a lot of ways, it seems to have a lot of the right properties so we'd like to see, you know, proteins behave correctly in the context of that better water model than this old tip 3p that doesn't even work with evolved. But when you finally run these things out to 10s of microseconds per system, you can start to see in fact, the water model does have an effect on the secondary structure. You know we say it doesn't you know it has only a minor effect on hydration free energies and such. Well it does have a noticeable effect in the long run on the secondary structure. And in fact, 19 SP this combination with OPC. You, you might be a cynic and say okay well it's because as partate, or maybe glutamate fell in the right spot. And, you know, otherwise had that had that not happened. And I've seen something very similar to 14 SP if only as partating glutamate had been in the right spots for that one. That would have been a, you know, pretty tight to the trend line sort of sort of slope as well. But I think, you know, and it's, it's encouraging to see that all the effort they put into 19 SP and to see a better model like this. They just refit torsions or replace torsions with C maps in that force field they they also took into account they they changed all the side chain torsions and they were taking into account some of these arguments I was making on the previous slides but they came up with their own solution to it which I think is probably even a better solution, because they incorporated salvation effects in the torsion fitting by finding a DFT method that looked very similar to GB or GB SA energetics. So the, the, the GB SA energy or energy profile the solution phase energy of these molecules, they found a DFT method along with the salvation correction that track that pretty closely and then they use that DFT method with salvation correction to do all of their torsion scans, and then consequently they use the GB SA as part of the internal energy against which they were fitting all those torsions so in the context of all that. They have their torsions fitted in, you know, in the context of some sort of salvation effect. And I think that probably had a very positive influence on their overall results. So now I'm going to transition to a little bit of just talking about options for improving these biomolecular force fields and the ones that really jump out before we go to polarization and things that will make it take at least four times as long to do a simulation. You can have additional models and to whatever limited degree you want so we can transition something like tip 3p or SPC into tip 5p. Or you can have these tabulated potentials, these CMAP terms you can, you can turn dihedral cosine series into cubic spline based map functions. And the other route that you can go is you can improve the fitting process so make the model more elaborate or improve the fitting process we've talked a lot about incorporating these salvation effects. Also, could we, when we think about the fitting, if we just do a least squares fit, we get one answer. We get the optimum least squares answer. But could we do a genetic algorithm or something around there? Could we find ways to conditions to perturb the least squares fit that we would actually get many degenerate solutions, some of which in fact are very different from one another, but all come very close in terms of the same figure of merit. So if we could do that, we could perhaps prune them using a diversity of different solutions to the entire molecular mechanics parameter set, prune those using experimental data and perhaps pick the winner. So the first thing to look at is I'm going to look at these extra points for elaborating the model. These are six frame styles of extra points and extra points in simulations sometimes called virtual sites. They do not have any maps, but they are, their positions are entirely determined as a consequence of the positions of frame atoms that do have maps. So if water is the frame atom, you've got the oxygen being the parent atom probably and you've got the two hydrogens being the other frame atoms. The simplest style here, style one, this is really good for putting things along a bond vector if you want charges there, which is actually a very good option, but it's also viable to do something like a sigma hole for for an organic halide. So to put an extra slightly positive charge out beyond the chlorine on a carbon chlorine bond along that bond vector, you're actually putting a positive charge out beyond what you think is a very electromegative chlorine atom. And that's creating what's called the sigma hole and that does very, very well in fact for improving electrostatic potential fits as well as hydration free energies. I'm not going to go too much into that. But that's a, that's a real success in terms of the way extra points can improve hydration free energies. Otherwise, the hydration free energies for these small molecules are largely a consequence of the overall dipole and improving the electrostatic potential fit using these extra points does not change the overall dipole molecule that much. So there are select cases in which case these extra points do improve hydration free energies. What I'm hoping is overall we can improve the details the nuances of the electrostatic potentials to get either better hydrogen bonding propensities or or also you know just better as a consequence better secondary structure propensities. You can look through all these other frames here. I really encourage people to look at the grow max manual that's where virtually all of this stuff came from. All of these things will now be implemented in the P memby package they are in the code and in a working branch, and they will be incorporated probably as a patch somewhere in the middle of the amber 20 release cycle. When we think about these extra points. A lot of people initially default to okay these are Lewis structures right or we can make Lewis structures out of them and this is what I what I think of is sort of taking the freshman chemistry off ramp in the computational chemistry and I think this comes about as a consequence. Of the fact that we have a lot of people who are very well versed in mathematics. They know a lot of computational science. They may not have actually taken as much chemistry in college, but the, you know, it's not to say that we've got lots and lots of education but the weight of that mathematical background I think sort of tends to pull us towards these these other models so tip five p. It's actually no not really much more successful than tip four p, even though most chemists would not think to put a, you know, to put a lone pair somewhere like at the, at the, you know, at a site sort of like in the elbow of that water molecule. But if you're looking only at these special chemistry positions, you're kind of missing out on a lot of stuff you could do with extra points. So if you if the electrostatic potential fit is your figure of merit, the lone pair Lewis structure positions often do not have that much effect, even in sulfur, where you've got the lone pairs as well as a quadruple. Even a little bit better off putting things along the bond centers. And it's kind of surprising, but in some sense that's where a lot of the electrons are in these molecules as well. So many extra points can have a moderate effect on the accuracy of that electrostatic potential fitting. If you have say 50% more particles in your monopole distribution so you have extra points along a number of the bond vectors, particularly in the polar groups. You've improved, you've increased the cost of your, of your simulation by a factor of perhaps two. But you have improved the fitting of the electrostatic potential by up to 40%. So how much effect that has in the accuracy, not just a hydration free energies but again, again a hydrogen bonding propensities will have to see no one's ever really made a an extensive extra points field for general biopolymers. There is a sugars extra point force field that seems to perform better than a nuclear charge only force field that works very well with tip 5p. But again, these are, it's, it's about 10 or 15 years old there's, there have been a lot of simulations with its sense, but there's a lot more development to be done in this area. The other way to elaborate these models that I want to do a little more of a deep dive into is the CMAPs.  If you look in any topology that has CMAPs it gives you the values at the grid points. And then the program is kind of trusted to fill in the details figure out how the cube explain interpolation works and roll with it. And that it sort of tells you right there that all it matters are the values the grid points right so if we know those. How do we get everything else. Well, you know the question is okay if we have some point anywhere in space. How do we then go back to the values the grid points and figure out what the exact value at our point of interest is because that's you know we have a particular position on the Ramachandran plot. How do we figure out what the value of the CMAP is given all these grid points. Now here is by cubic interpolation here's the formula for it all. And you can see here that if you just you know you have to plug in you know fill in plug in. I don't even know all these definitions here. But this is the concise compact form if you look in the code itself in amber or in charm, you're going to see a big 16 by 16 matrix doing this matrix multiply this is a more compact way to say the same thing. Okay, but what you can see here is that you need the values at the four surrounding grid points. So those would be no you can see these four surrounding grid points around here, you need delta x and delta y within the one bin. And you need to know the values of the derivative, the derivative and x or derivative and y and the cross derivative dx dy at each of those four grid points. Okay, so once you know all those things all the corner values, then you can do your matrix multiplication, you can come out with this a matrix and you can multiply it by your powers of delta x, and of course one is delta x to the zero. One is delta y to the zero. And with this big matrix vector multiply you come out with a scalar, you know, the, the, the power or the value of delta x delta y comes out from this big old formula so it essentially what this is saying is if I know the values of the grid points, and I know the derivatives at the grid points. I know what the value is anywhere in space. Well that's interesting because then if I wanted to fit a CMAP. I need, naively you think okay I need to know the values of the function of all the grid points and what we're going to see why that's actually trickier than it sounds a little bit later, but I'm going to show you my friend Arianna. She knows a lot of math. Okay, and this is something that she taught me about how to do cubic spline fitting and interpolation and thereby fit a cubic spline interpolated map using arbitrary data. So let's actually give me data anywhere in space, as long as it covers the map with reasonable density. I'm going to tell you what the ideal map should be to get that data. Let's put her in between LeBron and James and Dua and Abel and Enrique and Selena and Arnold and Ellie. Okay, and but for the small perturbation caused by the cause by James in this case which will not be a disaster. We could trace a cubic spline function over the tops of each of their heads, and it's practically symmetric. So Arianna can just look up and say, oh, the derivative at her point is zero. Okay, it's, it's, it's kind of just a symmetry argument, it's a no brainer. What happens though, if we mix up all these people now is Arianna going to get worried. Well, she knows a lot of math. So her formula is going to be, you come over here, you look at the height of the guy next to you, and you multiply by this constant I'm showing here.  And Arianna is just going to keep going like this side to side, if you will. And she can apply this stencil to get the value in fact of her derivative so she's multiplying by this one constant you see here and powers of this constant you see at the bottom. So it's an exponentially decreasing contribution from the heights of each of these people further and further away from her, that determines what her derivative is going to be but again her derivative is entirely a function of the heights of all the other people at these equally space positions around her. Now, Selena can do the same thing in fact Selena can apply the same stencil she's going to look left and right left and right, left and right. So, Ellie might be able to do the same thing we're getting really close to the boundary though and Arnold is going to realize oh he cannot terminate the series, but do I has new rules, and they sort of speak to the general case. So, with that, with the general case which I'm not going to go into too much because it's not needed for periodic boundary conditions but for some of the boundary conditions I'll talk about later it is. So, or actually Ariana help you work all this out. And with these formulas you can make stencils to get the derivatives at any point, any grid point as a function of the values of your of your tabulated function that all of the other grid points. Okay, and so that that implies by all of this math here you just run it back through this big long series of equations plug and chug. The surface value anywhere is a linear combination of the values everywhere. Okay, and so what this looks like in practice you can imagine. If you're right on a grid point. Well, what's the value of your function. It's 100% the value at that grid point. If you start to step off the grid point you start to have slight positive dependence on your your nearest neighbor values. And as you get directly over here on the very right if you if you get right in between for good points. The value of your function is an average of the four corners and then a little contribution from once further out. And what you're seeing here is kind of like it's like a wavelet distribution. Okay, but in fact the value at any arbitrary point depends on the values at all of the grid points. With exponentially decreasing decreasing importance. If you have like a 64 by 64 grid you can clip this series at 30 grid points in any direction. And if you do if you clip it right there, you've already got your answer to machine precision. In fact, so this is a very interesting way if you have if you have to spline tabulate something that you already know at regular intervals. You don't have to recalculate the values at very, very small discretizations and take a numerical derivative or something like that you can actually just take the values you've already got. If your function was very expensive to compute, and you can get your to within FP 64 machine precision, the correct answer just by looking at those values it's it's really remarkable what that's how it works as the math. So the upshot of this is that, again, I said naively, if you wanted to fit a CMAP, you might think you need to put your protein at every one of these grid points and Ramachandran space and nail it there. And then look at the energies and see what you got. If you try to do that, what you quickly realize is that, well, you can't quite restrain your molecule to any of these particular grid points it doesn't want to stay there and even if you put harmonic restraints on it. It's going to, it's going to drift off just a little bit. Now you could get really tricky and you could say okay well I'm going to, you know, move the restraints around the origin point of the restraints so that in fact all the molecules do fall on the grid points that would be very laborious but you could do it. What FF-19SB actually rolled forward with was something like the orange plot here. They had things that were very close to the grid points and in fact close enough I would say. Again, they still got very good results in their simulations, but they were rolling with this and thinking that they had to snap those values to the grid points. And what Arianna's math is telling us though is actually you could have something like this green data set which not coincidentally just looks a lot like the Ramachandra distribution of a canonical amino acid. But you could have amino acids in their native configurations. As long as you've got a smattering of coverage elsewhere all over the space, you don't want to leave big gaps in your data like two grid spacings. That's about as far as I would go. But as long as you have decent coverage and you have enough data points to inform what your map should be, any data set will actually do and it's just as valid as any other. So here are some glycine fitted C maps. I have my own force field fitting code again which is what Carl DeBiak and Anthony Bugatti have been using to fit their force fields. But I've taught it to do the C maps now. And again the C maps they're being done alongside in the same least squares fit as all the other torsions and all the angle parameters. So you do not have to fit one set of parameters and then another on top of it and keep propagating here that way it's all done in one fell swoop. But we can compare like the FF-19SB glycine C map to the ones that I fitted using some data. I just plucked the data from the FF-15IPQ training set. So there are some differences you can see in the spacing of the two blue peaks here in the middle and that's probably largely a consequence of the fact that the data is different. I mean I was using a different quantum method, mines and vacuum and theirs is in a solution phase environment. But it's, I think it's remarkable about 19SB. Their map is very nearly symmetrical except for a few small points here which I'm showing in these different plots to the right of each of the C maps. They did a very, very good job of curating and massaging and making sure these configurations were well optimized, well relaxed. They got a very symmetric map overall for glycine. Now obviously you don't expect symmetry in something like alanine or any of the other amino acids, but for glycine you should see this two-fold symmetry. The only place I really recover that well even with 6,000 data points spread all over the map is in the 8x8 C map. So I've made my fitting program so that I can fit 8x8, 12x12, 6x6, and if you take that you can make a 24x24 map out of any of those things without losing any of the information. So that's what the code is essentially doing. It's publishing 24x24 C maps even though I've fitted 8x8 or 12x12. You can see the 24x24 C map is wrinkled as a prune. It's definitely overfitted. But even the 12x12, you're seeing a lot of loss of symmetry despite the fact that I got 6,000 data points for only 144 fitted parameters. So the upshot here is that we have to be very careful how we design this data set. But I think probably overall a 12x12 map is a good compromise in terms of the detail it can capture. In terms of the figure of merit just getting the RMSE to these quantum energies, 12x12 is about as good as you can get. 24x24 is slightly better, but not much. It's very, very marginal. And again, the overfitting risk gets very, very high. So lastly, I just want to look at what can CMAPs do in terms of the RMS error? How can they help improve our figure of merit? Well, just looking at the FF19SB torsion set. So FF19SB deleted some torsions and replaced them with CMAPs. If I instead said, okay, now put those torsions back, delete the CMAPs, these are the RMS errors I would get for various systems along the X axis here. And I've just ranked them in terms of their overall ease of fitting, mostly like the single amino acid residues are down here on the left. And as you get further to the right, you get the charged amino acids and then the multi residue systems that I had in this. But this data actually comes, the fitting data is coming from the FF15IPQ data set. I'm fitting it with the FF19SB torsion space. Okay, and so then if I fit, if I fit new CMAPs using FF19SB CMAP space, that's when I get this blue and or this purple and orange line. So this is the effect of the CMAPs in almost all the cases they are doing better than torsions.  However, if I hit it with an even larger torsion space, so FF19SB actually truncated the torsion space quite a bit. They compacted a lot of their atom types back into one. They had this diversification in 14SB that they sort of rolled back. And I think that was the right move for 19SB. With the FF15IPQ, we went forward and maybe even pushed the diversification a little bit further. So if you have a very vast torsion space, as opposed to a CMAP space, what do we get? Well, the FF19SB CMAP space, again, does this blue and this purple and orange line. And the FF15IPQ torsion space actually seems to beat the CMAPs in some of these larger systems. But this is, again, this is like a beware kind of thing because it may indicate that 15IPQ is overfitted. Especially in these larger systems where we didn't have as much sampling and it was finding ways to cheat perhaps in the larger systems at the expense of the smaller systems, which you can see the expanded torsion space still does not do as well as the CMAPs on.  This is not the entirety of the fitting data for 15IPQ. There was a generational learning process in there. So I was using basically just the first generation of data and not the subsequent stuff. So this is 150,000 data points that you see across various systems. There were 250,000 data points in the entire training set for the finished 15IPQ. So hopefully some of this overfitting has been dealt with and we did see some of that effect during our fitting. But, you know, this is the moral here is we need to understand what the overfitting problem really is because when we step in the CMAPs, we're talking, if you look at CMAPs for 16 amino acids and you combine things like, you know, if you combine things like phenylalanine and tyrosine into one CMAP, you've got 9,000 parameters there, potentially. So we need to understand how much we can afford, how much fitting we can afford to do, and maybe what overfitting problem do we already have that we didn't understand. So I just want to wrap up by proposing some strategies in the bottom polymer force field development. I think at least for our purposes for open force field, we want to make our own polymer force field. We are porting some of the amber force fields into open FF format right now. So for our own force field, just to have a product that we demonstrate, you know, we can apply our methods to create a viable polymer force field that is expansible and easily incorporates, again, the hundreds of potentially unnatural amino acids. I think we should stick with common sets of nitrogen, hydrogen, carbon, oxygen, backbone charges, very much like the Cornell charge sets down and what we had to do at 1592, we found that to be the best choice. Then for if we have non-native residues, we should also pick some common atoms there and have some common charge sets, then pair those with common sets of backbone torsions. And really the reason to have common backbone charges is to make it so that the common backbone torsions can have an easier time fitting their part of the problem. Leaping and I have been discussing, we think that B3 lip with, I was using minimally augmented, but a DEF2, TZVPP basis set. Also, I didn't have it in the slide here, but back Johnson D3 dispersion corrections and we think that's a good balance of all the different forces that we need. And I would suggest using tripeptides as well as even some tetrapeptides, particularly for the charges where you've got this YAA, that's any amino acid of the serine, glycine, valine, alanine. So I'm putting a polar amino acid in there, I'm putting a glycine in there, but really making it so that your amino acid of interest, the X amino acid in the center there, it doesn't know always what is to either side of it when you're doing these charged set fits. So I think that's important. Now, I think it's also important to have a lot of confirmations of each amino acid. So in making the common sense of backbone charges and torsion parameters, I think we should extend that AD to DNA and RNA, probably a similar level of quantum theory will be sufficient. And then for carbohydrates, assigning common charges to each of the four most common elements based on what their neighboring atoms are. So carbon double bonded to another carbon with a nitrogen on the other side or carbon to a carbon to another carbon, you can see all these different permutations. There are probably at least 200 or 300 unique charges you could fit there, but I think we should probably try for something like that, and then do a direct fit to, you know, to ESP quantum data. But we can we can talk about making an AM one BCC like charge set or some sort of bond charge correction thing for for a even more expansive carbohydrate force field after that but I think it's it's quite feasible to take a few hundred common carbohydrate monomers and look at the different ways carbon oxygen and nitrogen can come together along with different hydroxyl groups and figure out some common charges but a set of a few hundred common charges to fit for that. And then future directions for force field development. I want to get back on this the CMAPS idea because now that we know how to fit CMAPS and they're actually not as scary as the the people who you know when making FF 19 SP I have to commend them for their inhibition because again looking at 9000 parameters how are you going to do it and having to generate the data with it as meticulous as they had to be about it. It's not nearly as scary as they had to deal with. And so, now that we know how to fit the CMAPS, and we know how to fit essentially any tabulated function. Well, let's think about, you know, it would be great if all our bounded parameters were good enough to just interpret raw quantum data. And we don't have to do this re-optimization. One of the things I've not mentioned at all in this talk is that when you take a torsion drive, what you're actually doing is doing a molecular mechanics optimization to relax away orthogonal what we hope we're on orthogonal degrees of freedom so we can isolate just the torsion or the set of torsions that we want to fit. Well, that changes the coordinates. So the coordinates from the molecular mechanics calculation give you an energy, and they correspond to an energy from the quantum calculation, but this is all being done because the quantum and molecular mechanics models don't agree in terms of what the bond and angle a high frequency degrees of freedom, the way those should behave. But what if our molecular mechanics parameters were good enough to follow the quantum model wherever it goes? Well, that would mean all we have to do is take the quantum optimized coordinates and feed them right into the molecular mechanics model and you've got it. Now for the IPQ force fields what we were doing, which actually works in some sense surprisingly is we were feeding molecular mechanics optimized coordinates into quantum single point calculations and what we were doing, you know, that we were justified by saying, well, this is where the molecular mechanics model is going to go in a simulation. So wherever it goes, let's just make sure that it's still tracking what the quantum energy of that surface would be. Now there's still a quantum energy, it's just not where the quantum model would necessarily have it go if quantum were driving the whole thing. But if we could make our molecular mechanics models better, which I think is sort of getting into this class two force field idea, you have bond and bond angle C maps. So with those things we could probably have enough detail to make these molecular mechanics models track the quantum very tightly. And then what we can do is, first of all, it would accelerate force balance fittings tremendously for very, very big data sets. There's no ambiguity into what coordinates and what energy you meant. So everyone's going to look and they're going to download the data set and they would look at it pretty much the same way. But the real advantage I think is we've been able to train to gradients at particular atoms. So we know we know what the force on this atom is supposed to be. We don't have to combine all the terms together and get an energy where you can have all sorts of compensatory effects. We know what every atom gradient should be and we have 30 times as much data coming out of every quantum calculation. So then in a very long view, you could even look at these C maps as a way to perhaps do hydrogen bonding. I mean, Dave Baker's group has been very successful with their Rosetta program and their tabulated hydrogen bonding potential. I think it's only about 12 grid points or so. I think they probably do a cubic spline interpolation of some sort, but again, any data set that has reasonable coverage of what hydrogen bonds look like could be enough. Now there's a lot of wrinkles here because the different hydrogen bonds, it all happens in the context of fitted charges. And who knows, you know, what the fitted charges on this whole hydrogen or that might be. How would you fit a common set of hydrogen bonding surfaces for that? Well, that's why this is sort of a long, long view in the future kind of thing. But I think it's time to start looking at this because once you have bond angle C maps, a hydrogen bond C map is hardly any different. So with that, I would like to acknowledge some of the people I work with at Rutgers. I'd like to also acknowledge NVIDIA. A lot of the people there have been very, very helpful for getting amber into the state that it is and allowing us to simulate at the level, the microsecond timescales that we do. And Scott Legrand is a person, he's absolutely a brilliant guy. He's, I'm sorry, he's not at Amazon. He's now back at NVIDIA. Brilliant guy, a little bit fickle, but a brilliant guy. And we're very, very glad to have him working with us again on the amber team. Thank you all.


And Mauritania's former president Mohammed Ud Abdelaziz has been jailed after a judge in charge of a corruption probe ordered his incarceration. The ex-leader says he has been persecuted in a bid to keep him out of politics but as vowed he would not go into exile. The spokesman of the former president's party, Jibril Bilal, confirmed his detention on Tuesday as he has twice gone before magistrate investigating the case since the charges including money laundering were brought in in March. The move comes days after the former leader refused to continue reporting to police after being put on the house arrest.


This is Stink Tech Hawai'i, Community Matters here. And welcome to Talk Story with John Wahee. We have an interesting topic and guest this afternoon. Our topic is discussing what we would like Hawai'i to look like be a hundred years from now. What should we be doing, I guess, to achieve this vision? Our guest is Dana Sato, and she is an assistant asset manager for the Kamehameha School. Yes. And that means you kind of run all the property on Oahu. On Oahu, Maui, Moloka'i, and Kau'i. So all of it. So this is interesting to me because you're kind of a really important person. But you are the kind of important person that normally we never get to see. Because you're in the main office for a major institution in Hawai'i, and you're doing important things regarding land. But why would you be in our show? And here we are. Today's topic we're going to talk about here. We should all show the speed. Where should Hawai'i be in a hundred years? This is, by the way, the Hawai'i Business Magazine, the August 2017 edition. Now, how in the world does an asset manager get to be part of this exercise? So there's actually 50 of us that are involved in this. And it's a huge number of people. So there are 50 people from across the state, right? Yes, across the Pai'ana, I know, yes, across the state that's involved in this. So there is a group of businessmen, local leaders. They're part of the Hawai'i Asia Pacific Association, who thought that we need to pull a group together in order for us to be able to set some long-term goals for Hawai'i. But we're a bunch of old people. It's how they started off with. Okay, so the people that were pushing all of this, the business guys said, we are not going to be around in a hundred years. We're going to be dead. So we should get a group of people who might be around in a hundred years from now. Well, not even a hundred years, because none of us would be that old. Well, you never know. Never know, maybe with technology and stuff. But certainly to select 30 and 40-year-olds who are local leaders. So a group of 50 participants were selected. And I'm assuming that this group would be a cross-section of Hawai'i's community. In fact, I think the names of the people who participated are actually found in the magazine. Yes. In the magazine. So you're on here somewhere? Yeah, I'm here somewhere. I think I'm pretty close to it. Number four. Number four. Only because they went by alphabetical order. So D is a good number to have. Okay, well, I'm still impressive. Number four. So they, somebody what? Somebody contacted you? How did you? Yeah, so when that group took a look at it, so then led by Duane Kurisu, who everyone knows is a local businessman. And other members of this HAPA group got together and then they brought in other groups. So they brought in Lauren Nami from Kamehameha Schools. And they brought in Earl Kava'a as a native Hawaiian expert. Yeah, Earl is a well-known cultural expert on things Hawaiian. Right. And so with that group, then they selected people to be members of this vision group, which is called I am Hawai'i. And there's a reason for that, as if you read about our overall vision, the reason why we said I am Hawai'i is the name of this group is because it's no longer a focus of just native Hawai'ians, just local Japanese, just local Koreans, just local Filipinos. We said, you know what? This vision statement has to apply to everyone. So I am Hawai'i, you are Hawai'i, others are Hawai'i. If you're in Hawai'i and this is important, this is part of what you need to work on. So that is something you evolved to. Yes. Right? Yeah. So I want to take you back in the beginning of all of this adventure.  I mean, did you walk in there saying, what in the world am I doing here? Or, oh, this is great. Let's get started. What was it like? So two things that went through my mind. First, what in the world am I doing here? Secondly, these are all young kids compared to me. Wow. So I'm not in the 30 to 40 category.  Because if you're, they were young kids compared to you, can you imagine what that makes people? Oh, we're the people going to die out anyway. So it was very interesting because a large majority of the people in this group I did not recognize. So walking into that room, then trying to hear this message about us working together toward a vision when you don't have Polina, when you don't have relationships with others, made it very awkward for myself and I know for others as well. So we've been working on this project for over eight months. Because it takes that long for you to get to know each other, but also to have the heart conversation. When you say heart conversations, what are some of the things that would come up? I mean like, obviously, we all see things maybe a little different, right? So I'm assuming that part of the discussion would be like, you know, I think that we ought to have more business and somebody's saying I think that maybe not. And so, okay, let's take a concrete example. I mean, I am sure that within your group there were people who think that the future of Hawaii needs to have a telescope on Mauna Kea, for example, right? And there are others who believe that maybe the essence of what we are as Hawaii or what you are as Hawaii means that we ought to protect our mountain top or something like that. So what happens when that kind of sub, or did that subject, for example, come up? That specific subject didn't necessarily come up, but very similar discussions happen. And so what actually started off was people were extremely courteous to each other in this group. Okay, that's a good beginning, because we're all from Hawaii, too. And we're all business people, we're all leaders. We're all looking at how we're trying to develop relationships with each other. We needed to sort of measure each other. And so that's why the earlier conversations actually were quite cordial, but did it actually get to the meat of the discussion? No. Okay. No. It took us being much more forthright with each other for us to really dive deep into what the issues were. And the native Hawaiian issues were a big issue, because many within the group did not understand what those issues were, because they didn't have to deal with them. As we sort of talked about in the group, you have the downtown financial people. And then you have the native Hawaiian issues on the outside. This group was intended to bring all of that together in the big table, because we have for so long tried to keep them separate. And not intentionally, but it just kind of happened. Right. And this group- So where does that put you? Because you occupy a very important business position, and somebody in your occupation has to be involved with business-type decisions on a daily basis, yet, given the institution you're working for, which is Kamehameha Schools, there's a kind of a trust, responsibility to native Hawaiians. And so you're sort of trying to balance all of this. But that balancing is actually part of our job, part of Kamehameha Schools' job. As we look at Aina, it cannot just be focused on one or the other, because Aina is so important to us on such a spiritual level as well. But at the same time, we have to be able to cultivate educational aspects, economic aspects, because we have to provide for the endowment, we have to provide for the education. So it's really not much different than what this group was trying to do, which is to find a balance. It's really all about balance. So one of the vision statements is specifically on vision of aloha. Oh, fantastic. Yeah. Let me tell you, first of all, you sat through like eight months of this, beginning nicely, that's typical in Hawaii, getting down to the nitty gritty. And at the end of it, what happened was, apparently, you created this, we're calling it a draft vision. And folks, if you want to see what the work that these people did, get a copy of the Hawaii Business Magazine, and it is their vision statement, 50 people meeting in Hawaii and created this vision statement. And they actually published it, as I understand it, so that people can review it and react to it. Yes. Yes. So that's important. You're looking for feedback. We're looking for feedback. We recognize that this is just a first step, but somebody had to take the first step. Somebody had to have the courage to take the first step. And so that's what we did. And the initiative. And the initiative. I mean, you know, one of the things about visions, as I know a little bit, was that, you know, what it takes is having one, and having one is not that easy. I mean, obviously, you worked on it. You occupy about, what, I don't know, maybe about 10 or 15 pages in here, which is, you know, amazing. The group that worked on all of this came up with nine sectors that they felt were important in Hawaii. And those nine sectors were the Aina, food, economy, energy, education, workforce and innovation, community health, government and infrastructure, and a vision of aloha. How did you decide what these sectors were? I mean, this is like hours of discussion. Yeah. When we first met, we actually met over a two-day period. And we actually worked on our vision statement to start off with individually. And you could see certain things coming out of that already from the mixture of the individuals in the room, that each of us came in with different backgrounds that had various interest areas. And that was probably a good reason why we were selected. In addition to our leadership roles that we play in our different organizations was also our areas of interest. So we have someone from the Department of Education there, an education. Kamehameh Schools is education. We've got the financial side, the business side. We have the banks that are involved in that section. So we have a sustainability person who has a focus on that. That's why we have a food and sustainability. So you have all these cross-conversations. You were particularly involved in one of these sectors, right? Yes. And that was? The INA sector. And which relates on a number of levels, not only because of your job, but because of your background working for Kamehameh Schools and your own interest, probably, as a Hawaiian. Well, I tell you, I want to get into the meat of all of this. And so we're going to be taking a short break for about a minute. And then we'll be back. And when we come back, I'd like to discuss what is this vision? We'll start with the INA one first. Yeah, sounds great. OK. This is Think Tech Hawaii, raising public awareness. Ted Rawson here, folks. You're a host on where the drone leads our weekly show at noon on Thursdays here on Think Tech. We talk about drones, anything to do about drones, drones, remotely piloted aircraft, unmanned aircraft systems, whatever you want to call them, emerging into Hawaii's economy, educational framework, and our public life. We talk about things associated with the use, the misuse, technology, engineering, legislation with local experts, as well as people from across the country. Please join us noon on Thursdays and catch the latest on what's taking place in the world of drones that might affect you. Welcome back to Talk Story with John Wahee. We have as our guest this afternoon, Dana Sato, who sat as a participant in the creation of a vision, which you can find in the Hawaii Business Magazine, where in the August 2017 issue, it says, where should Hawaii be in 100 years? Now, Dana, you were part of the AINA discussion and vision. And I find it very interesting that your vision statement is based on sharing the world a model of Aloha Aina, which is something important to native Hawaiians. And apparently, to all of the people that participated in your group, anyway. And so what it appears to be is that your vision was trying to balance, I guess, some of the best things about Hawaii and some of the challenges. How do we keep our farmlands? How do we keep things productive? One of the interesting parts of the vision was when you got down through the specifics. And in the specifics, you called for the creation of a planning body. And there would be some kind of planning. And it was types of experts that, in other words, would put together a planning body of all the experts that they will help us and so forth. And what's interesting to me was that planning agencies exist. The state has a land use commission. They're the city charters. And you talk about coordinating with all of these parties. But what immediately popped up to me was the fact that if you're dealing with long-range planning, obviously your group did not believe that any of these entities was really doing it. Yeah, you hit it right on the head of the nail right there, John. Our group was very much concerned with the fact that as each administration changes with the election, that what we find is we find a switch in the vision and the focus of the agencies that are related that way. And so with that type of change happening, how could we have a consistency in the vision moving forward? Still recognizing that the vision has to be a living document that changes as time goes, because it's impossible for us to know what's going to happen in 100 years. But at the same time, if the vision keeps flowing so much like this, then you really have no vision. OK, so there needs to be a kind of a consistency, kind of a long-term, I guess, stability for things to happen, which is why I think your vision suggests that, which is really interesting, that this planning agency made up of experts not be under the governor. It's not be sort of separate. Yes. And I guess that because governors obviously change every eight years. But who would this commission be accountable to if not the governor? Yeah, I guess as we were talking about it, we sort of looked at as a comparative, would be like the board of water supply in the county in which they're still connected, but not connected at the same time, and it allows for some autonomy for that agency. And so that's sort of how we looked at it this way. We know that it may not be perfect, but we wanted to at least put it out there in an effort that we could get comments from others that might help guide us to a more perfect type of vision with that. Well, one of the interesting things to me was the fact that the old Hawaiian culture, there was a kind of, in my opinion anyway, there was a kind of what I call meritocracy. And that is that if you want to be the top fisherman, then you better be the best fisherman. If you want to be the farmer, you better be the best farmer. There's a kind of thing, I guess, a kind of sense that that was the type of commission that you were heading for. Yeah, and that's true, because as you read the statement, we actually introduced back the idea of the Ahupua'a system, which is a system that's unique to Hawaii alone in management from the Malka to Makai, and the relationships within a Moku, like Waianae is a Moku. The Kona region of Oahu is a Moku. But there are relationships. I remember someone telling me before, and I can't remember where they read this, but when the foreigners first came to Hawaii, they said, there is no central metropolis. And the reason was is because there were all of these Ahupua'as, which were independent communities. And we looked at that as being, you know what? It worked, fed all the people. And there was a sense of order to that. And so our vision, in addition to that planning group, which would be sort of flying at the 30,000 foot level, is getting more communities involved on the Ahupua'a level. And people becoming expert where they were. Yes. I mean, that's the key. I mean, you wouldn't go and ask somebody from one Ahupua'a a question about the other Ahupua'a. Which, by the way, in our daily lives, nowadays, we think everybody can do everything. So anyway, so you got this there. I was just a little concerned, because you can have a meritocracy.  And they don't exist, you know? Well, and I think, so where this actually all started from was a question about what makes Hawaii different from anywhere else. What does make Hawaii different from anyone else? It's actually, as you know, as a governor, it's actually in our statute is the aloha spirit. That's what makes us unique from it. So as we worked on these vision statements, what was key to us was the fact that we need to resurrect in a much bigger, louder sense, again, aloha spirit and aloha. Because we see that as something that's unique to Hawaii, but slowly going away. Having the bumper sticker on your car is not enough, you know? So what we describe is that aloha is in our hearts. And it's our way to a better Hawaii, and it's our way to a better world. I know the bumper sticker thing.  Live aloha, exactly. And I say, as they cut in front of me, law to you too, you know? Exactly. So what you're talking about is like, I noticed that not only the vision on the aina, but all every one of these nine visions starts off with a discussion of values. And many, many times, the concept of aloha is constantly repeated. But not only aloha, laukahi, and many other Hawaiian values, it seems to me like the vision was, in a sense, based on a lot of the Hawaiian culture. Yes, it was. Yes, yes, it was. And it really all stemmed from the word aloha. Values all spin off from the word aloha. And what we all started to recognize and understand is that for any of this to go along, for the unity that we need under laukahi, that sense of unity through harmony comes from aloha. And we needed to also be able to look at what we're envisioning, not just for a better Hawaii, because that's too limiting. The way that we communicate in today's world, we can sit right here. Right, right. And we are communicating in China. Yeah, there'd be somebody maybe in China listening to us right now. Yeah, I hope so. You know, that would be interesting. By the way, I'm waiting for mail from the Chinese fans. Send us in, you know? But no, that's fantastic, because you're right.  You know, Bob Krause years ago wrote a book called The Island Way, which really influenced me. And in the book, he talked about the fact that there is a physiological difference between living on the continent and living in an island. And it had to do with the idea that when there was a lot of space, you can't afford to be a loner. You can't afford to go off and be Daniel Boone and living in the middle of the wilderness in Kentucky and all of that stuff. But when you have to see your neighbor every day and when you're living with limited resources, there is a whole different mindset to how you see the world and the solutions for the problems that you might face. There is a lot of that kind of thinking in these plans. Yeah, you're absolutely right, because that was specifically for our group that worked on the island. That was specifically an important thing for us. Is the recognition that we don't have infinite resources, but the opposite, that we have finite resources. And so when you have finite resources, you need to be able to recognize that you can't be using all the land for everything, that you have to be able to carefully manage and plan those lands to last into eternity. Because there is not as if, well, even off Hawaii Island, although we have additional land that is being built as we speak, those lands we know will not become productive lands for many thousands of years from now. So with the limited resources that we have, how can we best provide for people? We have to have that reciprocal relationship. See, I'm gonna bring a little bit of something else in. You grew up in Hawaii. Yes. Also in Wake Island. Yes.  Yes, yes. So anyway, but what it looks like the planet is becoming an island. And so the message, because as we have now 350 million people in the United States, they're no longer continents can be different than islands.  And it seems like this plan is right fit right into that. Yeah, because by focusing on taking care of what we have, we actually do impact the world and the future. Well, I wanna thank you not only for being with us today, but for participating in this. You and all of your participants, I think it's very, very important that we talk about values, that we talk about a Hawaii that's built on Aloha, which is what this document is about. So folks, get the Hawaii Business Magazine and read all about this and contribute your part. I'm hoping that there's another constitutional convention and you get a chance like we did in 1970 to incorporate this into our state's document. That would be awesome, John. That would be awesome. Well, thank you once again. Thank you, wow. Appreciate having you here.


So, the Kenya Film Commission is working on integrating the prisoners and equipping them with skills that would help them later in life through film production. The organization hopes the government adopts their program and helps them realize their plan. Correctional facilities commonly known as prison is an institution for the confinement of persons who have been remanded in custody by a judicial authority or who have been deprived of their freedom following conviction for a crime. Committee Maximum Prison is one of the correctional facilities well known by majority of Kenyans, if not all, by the virtue of perception and belief built in their minds.  A father, son, brother or an uncle to someone. Some have been locked in there innocently but also for the crimes committed. As fellow humans, they need to feel the sense of their being, though evil in many eyes. Kenya Film Commission has realized this niche and are using the slim opportunity in finding a natural intelligence that would have rather been stashed in the fortified walls of a prison. In the corporate social responsibility at committee Maximum Prison, the Kenya Film Commission has come up with a grand idea of integrating the inmates and incorporating them in the society through film making. During the event that was grist by representatives from the Ministry of ICT, Innovations and Youth Affairs, Principal Secretary Department of Correctional Services, Board Directors and CEO Kenya Film Commission, they launched training of trainers initiative that will see 50 wardens in Nairobi area and a goa 5-day capacity building workshop where they will be trained on basic film production. Kenya Film Commission CEO Mr. Timodio Wasing believes this skills transfer program will ensure the correction of facilities adopted as part of the programs offered to the inmates while in remand. And since there is lack of proper mechanism to empower the prison population and reintegrate them back into the society with skills to enhance employment or entrepreneurship, Mr. Wasing says they intend to bridge the gap. The wardens, they take care of the inmates every day, they train them on various capacity of skills within this particular environment. Film has not been part of their program and that's a key impetus for us to promote this particular item. Not only training but after training we're also setting up a resource centre at this particular facility. The resource centre will provide materials that are necessary to produce a film. We want to provide this institution with a production unit in terms of cameras, sound, a complete studio that will enable those who have been trained to practice and train the inmates. Prison warden Mutembe appreciated the initiative and affirmed his commitment in working with the Kenya Film Commission. We are very delighted to have the Kenya Film Commission come here to launch a film pilot project. Why are we excited? We're excited because as we endeavor to ensure we go up to our mandate, prisoners need skills and of course the Kenya Film Commission will develop skills and our next talents or nature talents that will assist our inmates once they are used they have some skills that they can use to secure self-employment. We are very grateful for the Kenya Film Commission for having committed maximum to be an earlier where they have their first pilot project and we are looking forward to collaborating with the Kenya Film Commission. Thank you. The film industry continues to play a key role inspiring economic growth and realization of vision 2030 through infrastructural development, tourist attraction, investments and employment creation. Kenya Film Commission is fully in touch with the needs and aspirations of its key target audience and it achieves this through various campaigns. The training of trainers workshop is scheduled to kick off on 23 March 2020. The film Kenya Capture Africa is the slogan for the Kenya Film Commission and integrating prisoners like other members of the society. It thus means we are heading in the right direction as a country. Reporting for I-254 TV, I'm Dereva Hilewi.


Good morning, anybody here from are there any high school students here? Is it all how many that's what I thought okay? What high school you guys with I? Love coming to North Dakota. It's become for me almost an adopted state Part of it is I had asthma as a kid and I think for some reason the Great Plains the Landscape here always appeals to me the sense of openness. I get a little bit claustrophobic Places, so the just driving here sort of Triggers a kind of freedom mechanism. I know you guys in high school here Many ways you always I grew up in Perry'sburg, Ohio I was wanted to get out of Perry'sburg I know a lot of people sometimes want to get out of their hometown and get out there in the world But there you live in a very special place. This is a very special University dick on I was telling the president of the school that Two of the great American authors have commented on just where we're at right now One was Jack Kerouac in his on-the-road journals Does anybody read on the road by Jack Kerouac? Well, if you you should read it It's a great American novel, but he's talked about the people of Dickinson I Edited a book of Kerouac journals called windblown world and he said there are no finer people than in Dickinson, North Dakota And he talked about seeing the bus stuck in the snow Now all the people pulled together to get the bus out and it's a beautiful homage and at the end of it He said that he wants to be buried in Medora, North Dakota He's instead Kerouac buried in low, Massachusetts where he grew up and also the great Erskine Caldwell author of tobacco road Had it wrote about being here at Dickinson actually coming to Dickinson State University And he's the tobacco road was the best-selling novel of the 1930s sort of one of the 20th century classics so these two major authors have all commented on life in Dickinson Before I talk I want to ask a friend of mine to stand up. She's somebody. I love a great deal I've adopted her as a surrogate mother She's person who's been an impresario along with her late husband Harold Schaefer of Medora and Creating this sort of essence there in Medora of of the the Western frontier of the Badlands at Theodore Roosevelt So no finer national park and I go to all of them Then what happens at Theodore Roosevelt National Park between both units and the power of the Badlands and the fact that tourists could come and see buffalo see prairie dogs see antelope and the person I think Possible for keeping the spirit of Western Dakota Northwestern North Dakota alive as Shiloh Schaefer and would you stand just for one minute silent? Thank you. I don't want to get into It's an endless proposition to To start naming people then you end up leaving people out but my colleagues that are here Many of them have just written Candice and Patricia fabulous books on Theodore Roosevelt that are just getting rave reviews everywhere And I know some of you can't keep up on the literature of this Some of you've never read a book on Theodore Roosevelt, but we're walking in in high cotton as they say we have really outstanding Scholars here and tweed Roosevelt just to connect to the family and to hear his adventures And he knows so much about the personal TR and never ceases to Impress me and he's just one of those good guys that once you know him in your life He stays in your life and Clay, thank you. I know how much work you do and what you're bringing to here clays a Rhodes Scholar Somebody who could be anywhere. He chose to come back to North Dakota and he's sort of become the In many ways the conscience of the little Missouri River And somebody who works to keep people like Jefferson and TRs image alive around the country and I'm grateful for that look I wanted to talk today about Conservation at Theodore Roosevelt Theodore Roosevelt as naturalist we heard a lot about blood sport We heard a lot about hunting. I know there are hunters here It's a big part of Theodore Roosevelt's conservation and it intertwines hunting and conservation with groups like the Boone and Crockett Club and his life but the Beginning of TR saga and it makes some of you guys wonder if you're keeping diaries or journals Just imagine Theodore Roosevelt was eight years old and he already started keeping an account of his life in But mainly his naturalist life at eight years old He went down to a war front in New York and got a head of a seal a skull He saw the full seal dead seal laying there at a fish market.  He kind of wanted the seal eventually. He negotiated to get the skull And that became the beginning of Theodore Roosevelt's own natural history museum that the young TR started collecting animals and birds nest eggs Skeletons of any kind of animal possible and he would do detail study and recording on this starting at eight years old The late John Gable used to always tell me TR's first writing was about birds at eight And then he wrote about birds on his deathbed This was a man who didn't just like nature. He dedicated To conservation and he was our great naturalist president now the journey We have to ask is why is it kid at eight years old collecting all these things all children like animals All you have to do is look at Disney or or any cartoon network and you can see how kids are attracted to anything dealing with animals But Roosevelt had two unique role models in his life early on which gave him an advantage a head Naturalist first was his father Who created the Museum of Natural History in New York? If you guys go to New York, you see the great our country's great natural history museum Roosevelt's father created in there in their parlor in Manhattan were the first meetings to create this so you talk about an enduring gift to the United States from the Roosevelt family This this natural history museum. It's par excellence. There's nothing Remotely like it, but his father was in some ways a very prudish Puritanical Philanthropist he was not somebody known to have a wild streak. He was a dedicated and devoted family man He was a man about integrity and about honesty Somebody asked me about American presidents, which I wrote about the one thing. I'll tell you you learn about TRs He always told the truth You don't find Roosevelt lying and that's the number one lesson of him as president always call it And you don't go wrong in in history. He's a role model in that regard He made mistakes in many ways. We confound on theater Roosevelt aspects of his imperialism By today's standards, there's a racism in some aspects of what TR was about But but nobody can ever challenge his bedrock honesty and in the courage of his convictions Now the other side beyond his father. There's a lesser-known figure and that's his father's brother his uncle uncle Rob Roosevelt Robert Roosevelt was a grand eccentric of mid 19th century America at the time of the Civil War and shortly after Uncle Rob was considered the Audubon of America He wrote books about fish In in New England. He wrote about Canada. He was an expert on on fish and birds Now remember if you cut to America in the 1870s tear the the Roosevelt's love of natural history is neither operating in a bubble We know that Thomas Jefferson was a great naturalist There was a there was a course Audubon and I hope you all know when you see those Audubon bird illustrations Audubon would actually kill the game. He'd shoot the bird do taxidermy get it stuffed and then draw it from the stuffed figure And but there's this tradition of Audubon and uncle Rob as part of it Robert Roosevelt theater Roosevelt's uncle Created the first fish hatchery in the United States He ran for Congress served at one term with one idea in mind and that was to repopulate the Hudson River of with shad The fish that had been been killed off from overfishing. So today you see people with save the whale With uncle Rob. It was saved the shad in New York


So I am back with a little bit of Cyberpunk news today and while some of it is good and some of it for us fans who continue to wait for Cyberpunk on that next gen, well it's kinda bad. How's it going guys, my name is DPJ and if you enjoyed the video leaving a like really helps out and if you like what you see and want to see more be sure to subscribe. So Cyberpunk in terms of the general game is a much much better game now, it's in a much better spot than what it was at release. And it would have been crazy to imagine at that time of release that even a year later things still wouldn't be perfect and let's face it, as much as I love the game, even within it's kind of broken state, for me it's far from that finished product it should have been. So the bad news, coming straight out of the H1 2021 shareholders results call which was last Wednesday I do believe, the Senior Vice President of Business Development Michael Nawodowski basically said that the PS5 and Xbox Series X may miss out on their own versions of the game this year. He said and I quote, the target is to release the next gen versions of Cyberpunk 2077 later this year. He said, at the same time, keeping in mind the lessons we have learned during the past year and taking into account that this project still remains in development, we can't say with full certainty that the production schedule will not change. As with Cyberpunk 2077 our goal is to release that game still in late 2021, however similarly the development process is still ongoing and we cannot be absolute dead certain that the release schedule will not change. But for the time being we definitely are aiming for both titles for late 2021 and I don't want to be more specific at this moment in time. Now I have heard previous excuses and false promises in the past from CDPR so this statement doesn't fill me with any confidence at all. A next gen version is something I am truly excited to see as I've played from day one on that next gen console and well on PC but on console it's never lived up to those expectations of how a game like this could play because I'm basically playing a backwards compatible port. So I'm excited to finally see a next gen version and if I'm honest with you because this is the first major news I've heard in a while on that next gen port I did think deep down that a delay might come. Now although this isn't yet set in stone, just know it's something that could happen. CDPR did confirm that all the third of the company is working on Cyberpunk for next gen versions as well as support for the original game. The remaining development staff are building the game's first expansion, Gwent and other unannounced projects. So are there people still working on it and only time will tell guys. In my opinion all is not lost with Cyberpunk and although I don't think it will ever be the game it planned to be it can still be a game that makes an impact on the gaming world for the good reasons as well as the bad. Ok so moving on. So this news actually found out via a discord I'm in and it's dedicated to Cyberpunk Months as you may know. I had a blast testing and showcasing mods for PC on this game, some of the best times I've had in the game I'm not going to lie. But the good news is here, CDPR have actually hired a few of these game modders to work on a game itself. Although I know this for some people isn't anything major, for the people that know they know. Other of these modders have changed the game for the better in such a short amount of time due to simple mods they have come up with. And having these fresh eyes on this project from people who know what they're doing in my opinion is something great. This news was dropped on the discord and already so like I said I saw it on my discord I don't think CDPR themselves have come out and said anything but it is legitimate news. I'm personally excited for the future of the game, I mean I've got way past the stage now of expecting things on time and I'm just patiently waiting for a game that works flawlessly. Whether that's this year or next, I mean no rush at all. Will it have one of those No Man's Sky combats? I'm not too sure about that because No Man's Sky right now is absolutely incredible. What we will see, we will see. And there we have it P4. We have come to the end of the video. If you guys enjoyed it, leaving a like really helps out. If you're new around here and want to see more Cyberpunk be sure to subscribe and if you never want to miss a video I upload you can turn notifications on by hitting that bell button. But guys thanks as always for stopping by and hopefully I will see you on that next one.