title: On the role of electrostatic interactions in the design of protein-protein interfaces.
abstract: Here, the methods of continuum electrostatics are used to investigate the contribution of electrostatic interactions to the binding of four protein-protein complexes; barnase-barstar, human growth hormone and its receptor, subtype N9 influenza virus neuraminidase and the NC41 antibody, the Ras binding domain (RBD) of kinase cRaf and a Ras homologue Rap1A. In two of the four complexes electrostatics are found to strongly oppose binding (hormone-receptor and neuraminidase-antibody complexes), in one case the net effect is close to zero (barnase-barstar) and in one case electrostatics provides a significant driving force favoring binding (RBD-Rap1A). In order to help understand the wide range of electrostatic contributions that were calculated, the electrostatic free energy was partitioned into contributions of individual charged and polar residues, salt bridges and networks involving salt bridges and hydrogen bonds. Although there is no one structural feature that accounts for the differences between the four interfaces, the extent to which the desolvation of buried charges is compensated by the formation of hydrogen bonds and ion pairs appears to be an important factor. Structural features that are correlated with contribution of an individual residue to stability are also discussed. These include partial burial of a charged group in the free monomer, the formation of networks involving charged and polar amino acids, and the formation of partially exposed ion-pairs. The total electrostatic contribution to binding is found to be inversely correlated with buried total and non-polar surface area. This suggests that different interfaces can be designed to exploit electrostatic and hydrophobic forces in very different ways.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University, 630 West 168th street, New York, NY 10032, USA.
authors.forename: Felix B
authors.initials: FB
authors.lastname: Sheinerman
authors.forename: Barry
authors.initials: B
authors.lastname: Honig
mesh_terms: D000937:Antigen-Antibody Reactions; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D004355:Drug Stability; D006639:Histidine / Q000737:chemistry; D019382:Human Growth Hormone / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007477:Ions; D008433:Mathematics; D009439:Neuraminidase / Q000737:chemistry* / Q000378:metabolism; D009975:Orthomyxoviridae / Q000201:enzymology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry* / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000737:chemistry* / Q000378:metabolism; D055672:Static Electricity; D013816:Thermodynamics; D020827:rap1 GTP-Binding Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D007477:Ions; D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; D006639:Histidine; D019908:Proto-Oncogene Proteins c-raf; D009439:Neuraminidase; D020827:rap1 GTP-Binding Proteins