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Physical Sciences Division
Research Highlights

October 2008

Melding Experiment and Theory Sheds Light on Molecular Recognition

Research based on collisions thrives on integration with theory

Julia Laskin Julia Laskin and her team from Pacific Northwest National Laboratory combined experimental and computational work to get this previously unknown answer. Enlarged View

Results: For the first time, scientists have determined in the laboratory how much energy is needed to release a large complex molecule from its target without solvent present. The team from Pacific Northwest National Laboratory combined experimental and computational work to get this previously unknown answer.

Why it matters: Antibiotics, enzymes, and other complex molecules can selectively find their targets, even when the targets are as rare as a needle in a haystack. To understand how these molecules perform this feat of biorecognition, scientists need to know the energies involved in the interactions. This knowledge could lead to designer molecules that break apart plants to release precursors for bio-fuels or specially designed nanomaterials for environmental remediation or sensors.

Methods: The researchers began with vancomycin, a well-characterized antibiotic that serves as a model for biorecognition studies, where molecules identify specific targets. Vancomycin binds to its target, a tiny protein on the bacteria's outer wall. This binding involves relatively weak bonds known as noncovalent bonds.

As a first step, the researchers added a proton to vancomycin and bound it to a model of its target. Using a model, the team could focus on the bond and not the baggage brought by the bacteria. The complex was transferred into the gas phase, removing any interference from troublesome solvents.

Second, the researchers allowed the antibiotic-peptide complex to collide with a surface inside a specially designed mass spectrometer in the Department of Energy's EMSL, a national scientific user facility at PNNL. This technique is called surface-induced dissociation. The molecular complex broke. The noncovalent bonds snapped and released the target protein. The team measured the time and energy involved in this and other reactions. They used detailed modeling of their experimental data to determine the binding energy between the antibiotic and the protein.

This method allowed the researchers to determine for the first time the binding energy between the two molecules as 30.9 ± 1.8 kcal/mol, a number previously unknown.

Next, researchers calculated the binding energy using theoretical calculations. The calculations resulted in a binding energy of 30.3 to 36 kcal/mole. This is a good match to the experiments. Also, the calculations provided insights into the behavior of the complex. First, the added proton played a role in binding the antibiotic to the target. Second, both the vancomycin and the target rearranged themselves when the complex breaks apart. The complexity of these calculations required the power of EMSL's supercomputer to solve.

What's next? The researchers plan to continue studying the binding energy of other complex molecules using surface-induced dissociation and theoretical calculations.

Acknowledgments: This work was funded by a grant from the Separations and Analysis Program within the Chemical Sciences Division, DOE's Office of Basic Energy Science.

The theoretical calculations were done using the supercomputing resources, NWChem, and Ecce at the Department of Energy's EMSL, a national scientific user facility at PNNL. Experiments were done using a specially configured 6-Tesla Fourier transform ion cyclotron resonance spectrometer in EMSL.

This work supports PNNL's mission to strengthen U.S. scientific foundations for innovation by developing tools and understanding required to control chemical and physical processes in complex multiphase environments.

Reference: Yang, Z, E Vorpagel, and J Laskin. 2008. "Experimental and Theoretical Studies of the Structures and Interactions of Vancomycin Antibiotics with Cell Wall Analogues." Journal of the American Chemical Society; ASAP article: DOI 10.1021/ja802643g.

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