Computer simulation of protein-protein association kinetics: Acetylcholinesterase-fasciculin

Computer simulations were performed to investigate the role of electrostati c interactions in promoting fast association of acetylcholinesterase with i ts peptidic inhibitor, the neurotoxin fasciculin. The encounter of the two macromolecules was simulated with the technique of Brownian dynamics (BD), using atomically detailed structures, and association rate constants were c alculated for the wild-type and a number of mutant proteins. In a first set of simulations, the ordering of the experimental rate constants for the mu tant proteins was correctly reproduced, although the absolute values of the rate constants were overestimated by a factor of around 30. Rigorous calcu lations of the full electrostatic interaction energy between the two protei ns indicate that this overestimation of association rates results at least in part from approximations made in the description of interaction energeti cs in the ED simulations. In particular, the initial ED simulations neglect the unfavourable electrostatic desolvation effects that result from the ex clusion of high dielectric solvent that accompanies the approach of the two low dielectric proteins. This electrostatic desolvation component is so la rge that the overall contribution of electrostatics to the binding energy o f the complex is unlikely to be strongly favourable. Nevertheless, electros tatic interactions are still responsible for increased association rates, b ecause even if they are unfavourable in the fully formed complex, they are still favourable at intermediate protein-protein separation distances. It t herefore appears possible for electrostatic interactions to promote the kin etics of binding even if they do not make a strongly favourable contributio n to the thermodynamics of binding. When an approximate description of thes e electrostatic desolvation effects is included in a second set of ED simul ations, the relative ordering of the mutant proteins is again correctly rep roduced, but now association rate constants that are much closer in magnitu de to the experimental values are obtained. Inclusion of electrostatic deso lvation effects also improves reproduction of the experimental ionic streng th dependence of the wild-type association rate. (C) 1999 Academic Press.