Evaluation of the kinetics of electrostatically steered protein dimerization using Weighted-Ensemble Brownian dynamics

A number of recent studies have examined the roles of charged amino acid re sidues in guiding protein association. Motivating these studies is the hypo thesis that patterns of charged amino acid residues cooperate electrostatic ally to assist in orienting the interacting proteins, increasing the rate o f association, This 'electrostatic steering' effect is enhanced by decreasi ng the ionic strength in the surrounding solvent, and has been shown experi mentally to raise the association rate coefficient several-fold. The presen t study employs a recent advance in the computational methodology of Browni an dynamics simulation to dissect the process of electrostatic stet:ring in two model systems. A dimeric hemoglobin, whose constituent monomer is pred icted to dimerize rapidly, and the adenosine diphosphate (ADP)-ribosylation factor ARF-1 from rat, shown to dimerize only at high concentrations, were approximated as spheres and the effects of their respective patterns of su rface charges on dimerization kinetics were compared. The hemoglobin charge pattern yielded higher association rate coefficients consistently than did that of ARF-I and the difference was especially pronounced when the charge patterns of each protein were applied to spheres the size of the other pro tein, In future work planned for this system, the detailed dissection of th e roles of individual charges within the patterns on the surfaces of these proteins will indicate how the respective charge patterns dictate the obser ved association rates. (C) 2000 Elsevier Science B.V. All rights reserved.