Abstract
Protein-protein interactions play an essential role in cellular processes. Certain proteins form stable complexes with their partner proteins, whereas others function by forming transient complexes. The conventional protein-protein interaction model describes an interaction between two proteins under the assumption that a protein binds to its partner protein through a single binding site. In this study, we improved the conventional interaction model by developing a Multiple-Site (MS) model in which a protein binds to its partner protein through closely located multiple binding sites on a surface of the partner protein by transiently docking at each binding site with individual binding free energies. To test this model, we used the protein-protein interaction mediated by Src homology 3 (SH3) domains. SH3 domains recognize their partners via a weak, transient interaction and are therefore promiscuous in nature. Because the MS model requires large amounts of data compared with the conventional interaction model, we used experimental data from the positionally addressable syntheses of peptides on cellulose membranes (SPOT-synthesis) technique. From the analysis of the experimental data, individual binding free energies for each binding site of peptides were extracted. A comparison of the individual binding free energies from the analysis with those from atomistic force fields gave a correlation coefficient of 0.66. Furthermore, application of the MS model to 10 SH3 domains lowers the prediction error by up to 9% compared with the conventional interaction model. This improvement in prediction originates from a more realistic description of complex formation than the conventional interaction model. The results suggested that, in many cases, SH3 domains increased the protein complex population through multiple binding sites of their partner proteins. Our study indicates that the consideration of general complex formation is important for the accurate description of protein complex formation, and especially for those of weak or transient protein complexes.
Highlights
Protein-protein interactions are essential in virtually every process within cells
We developed a Multiple-Site (MS) model, which was derived based on the formalism for the standard free energy of binding [25] and used for describing Src homology 3 (SH3)-mediated interaction, in which an SH3 domain recognizes its partner protein through closely located multiple binding sites on the surface of the partner protein by transiently docking each binding site
We applied the model to the analysis of SPOT-synthesis data of various SH3 domains
Summary
The rate of protein complex formation is governed by diffusion and geometric constraints, followed by a structural reorganization to form a stable complex [1,2]. A transient complex, the ‘‘encounter complex’’, accelerates the formation of the protein complex [3]. The encounter complex is primarily formed from charge-charge interactions between proteins and operates by reducing the conformational search space [4]. Protein complexes that are bound by noncovalent interactions are in dynamic equilibrium (i.e., they continuously switch between free and bound states) [5,7]. If a peptide ligand has multiple binding sites that are located close to one another, an encounter complex would increase the speed in such a way that a protein shuttles between each binding site in the peptide ligand [7]
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