The existence of several protein/ligand complexes which form from their constituent molecules at extremely high rates has stimulated interest in the mechanisms by which these components recognize their interacting partners. For several of these complexes, 'electrostatic steering' has been implicated as a major driving force: the charged amino acid residues on the surface of the protein serve to attract the ligand to its binding site in the correct orientation, enhancing the rate of association. In the present work, a dimeric hemoglobin has been examined using Brownian dynamics simulation with respect to the roles played by the charged amino acid residues on the surface of each monomer. The association reaction was simulated after converting each charged residue to an uncharged substitute, and the bimolecular association rate coefficient was compared with that of the wild-type monomers. Those substitutions giving the greatest changes were not limited to certain portions of the protein, but were scattered about the surface, lying most often along the lateral edges of the monomers. The role of each of these charged residues appears to be possible to rationalize from the electrostatic environment in which the residue is located, and may either be to accelerate or retard dimerization. The observed association rate coefficient is the sum of these favorable and unfavorable interactions during the association process, and shows that while the interactions between charged residues are favorable in the complex, they may provide small energetic barriers to association during the reaction. © 2001 Elsevier Science B.V.
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