Electrostatic contributions to protein–protein interactions: Fast energetic filters for docking and their physical basis

Abstract

The methods of continuum electrostatics are used to calculate the binding free energies of a set of proteinprotein complexes including experimentally determined structures as well as other orientations generated by a fast docking algorithm. In the native structures, charged groups that are deeply buried were often found to favor complex formation (relative to isosteric nonpolar groups), whereas in nonnative complexes generated by a geometric docking algorithm, they were equally likely to be stabilizing as destabilizing. These observations were used to design a new filter for screening docked conformations that was applied, in conjunction with a number of geometric filters that assess shape complementarity, to 15 antibody-antigen complexes and 14 enzyme-inhibitor complexes. For the bound docking problem, which is the major focus of this paper, native and near-native solutions were ranked first or second in all but two enzyme-inhibitor complexes. Less success was encountered for antibody-antigen complexes, but in all cases studied, the more complete free energy evaluation was able to identify native and near-native structures. A filter based on the enrichment of tyrosines and tryptophans in antibody binding sites was applied to the antibody-antigen complexes and resulted in a native and near-native solution being ranked first and second in all cases. A clear improvement over previously reported results was obtained for the unbound antibody-antigen examples as well. The algorithm and various filters used in this work are quite efficient and are able to reduce the number of plausible docking orientations to a size small enough so that a final more complete free energy evaluation on the reduced set becomes computationally feasible. Keywords: Protein-protein interactions; protein docking; electrostatic interactions; scoring functionsThe ability of many proteins to form specific stable complexes with other molecules is fundamental to all biological processes. Understanding the structural and physical chemical factors that determine affinity and specificity in complex formation is thus a problem of considerable general importance. The ability to predict the structure of complexes from a knowledge of the structures of the individual subunits alone, the docking problem, provides a test of our level of understanding but also has many practical applications. Protein/small molecule docking is a central component in most structure-based drug design strategies, and, for example, a solution of the protein-protein docking problem would allow the prediction of the structure of multidomain proteins from the structures of the individual components.Docking is generally divided into the bound and unbound problems. The bound problem attempts to reproduce the structure of a complex, assuming that the conformation of the individual subunits in their monomeric states is identical to their conformation in the complex. This assumption is removed in the unbound problem, which begins with the observed conformations of the free monome...

Development and validation of an empirical free energy function for calculating protein–protein binding free energy surfaces

“…1 and Tables 1 and 2 are obtained. Thus, solvent inaccessible intermolecular hydrogen bonds appear to be one of the key interactions that distinguishes native from non-native protein-protein complexes and this inference is in good agreement with at least one previous docking study [7].…”

Computational Methods for Biomolecular Electrostatics

“…Electrostatic interactions also play an important role in determining thermodynamics of binding; i.e., binding affinity (Novotny and Sharp, 1992;Fersht, 1993, 1995;Zhu and Karlin, 1996;Chong et al, 1998;Sheinerman et al, 2000;Norel et al, 2001;Rauch et al, 2002). Substrate binding allows the formation of (potentially) favorable charge-charge interactions between the substrate and target, as well as stabilizing specific salt-bridges and hydrogen bonds Fersht, 1993, 1995;Chong et al, 1998).…”

Solution Structure of Ectodomains of the Insulin Receptor Family: The Ectodomain of the Type 1 Insulin-Like Growth Factor Receptor Displays Asymmetry of Ligand Binding Accompanied by Limited Conformational Change

“…We found that the domain interfaces of IGF-1RΔβ (model) are comparable in computed buried surface area to their respective partners in IRΔβ (cryst) and that their respective shape complementarity parameter 26 S c is also acceptable (data not shown). We have also computed the buried charge κ score, 27 which provides a qualitative estimate of the electrostatic complementarity of the interaction interface between the two proteins-interfaces with unfavorable electrostatic complementarity are characterized by a negative κ score. The interface between the L1 domain of one monomer and the FnIII-2 and FnIII-3 domains of the other monomer in IRΔβ (cryst) has a κ score of 0, whereas in the model of IGF-1RΔβ (model) , the κ score is 2.5 for this interface.…”