 One issue with SHAKE is that the number of iterations required to reach a certain level of convergence does rise as molecular geometry becomes more complex.To reach 64 bit computer accuracy (a relative tolerance of formula_44) in a typical molecular dynamics simulation at a temperature of 310K, a 3-site water model having 3 constraints to maintain molecular geometry requires an average of 9 iterations (which is 3 per site per time-step).A 4-site butane model with 5 constraints needs 17 iterations (22 per site), a 6-site benzene model with 12 constraints needs 36 iterations (72 per site), while a 12-site biphenyl model with 29 constraints requires 92 iterations (229 per site per time-step).