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Electrostatic complementarity at the interface drives transient protein-protein interactions

Understanding the molecular mechanisms driving the binding between bio-molecules is a crucial challenge in molecular biology. In this respect, characteristics like the preferentially hydrophobic composition of the binding interfaces, the role of van der Waals interactions (short range forces), and the consequent shape complementarity between the interacting molecular surfaces are well established. However, no consensus has yet been reached on how and how much electrostatic participates in the various stages of protein-protein interactions. Here, we perform extensive analyses on a large dataset of protein complexes for which both experimental binding affinity and pH data were available. We found that (i) although different classes of dimers do not present marked differences in the amino acid composition and charges disposition in the binding region, (ii) homodimers with identical binding region show higher electrostatic compatibility with respect to both homodimers with non-identical binding region and heterodimers. The level of electrostatic compatibility also varies with the pH of the complex, reaching the lowest values for low pH. Interestingly, (iii) shape and electrostatic complementarity behave oppositely when one stratifies the complexes by their binding affinity. Conversely, complexes with low values of binding affinity exploit Coulombic complementarity to acquire specificity, suggesting that electrostatic complementarity may play a greater role in transient (or less stable) complexes. In light of these results, (iv) we provide a fast and efficient method to measure electrostatic complementarity without the need of knowing the complex structure. Expanding the electrostatic potential on a basis of 2D orthogonal polynomials, we can discriminate between transient and permanent protein complexes with an AUC of the ROC of 0.8.

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