Spatial organization of hydrophobic and charged residues affects protein thermal stability and binding affinity

Desantis, Fausta (2023). Spatial organization of hydrophobic and charged residues affects protein thermal stability and binding affinity. Postgraduate Research Poster Competition, The Open University.

Abstract

What are the molecular determinants of protein-protein binding affinity and whether they are similar to those regulating fold stability are key issues in molecular biology having important implications both under a theoretical and an applicative perspective. Here, we analyze chemico-physical features on a large dataset of protein-protein complexes of known experimental binding affinity data and compare them with a set of monomeric proteins of available melting temperature data. Firstly, we probed the spatial organization of protein intra- and inter-molecular interaction energies among residues showing that strong Coulombic interactions associate with a high protein thermal stability, while strong intermolecular van der Waals energies correlate with protein-protein binding affinity. Given the role of van der Waals interface interactions in binding affinity, we focused on the molecular surfaces of the binding regions and evaluated their shape complementarity, employing a 2D Zernike polynomials expansion, thus managing to quantify the correlation between local shape complementarity and binding affinity. Moreover, considering the solvent interactions via the residue hydropathy, we found that the hydrophobicity of the binding regions dictates their shape complementary. These results pave the way to the fast and accurate prediction and design of optimal binding regions as the 2D Zernike formalism allows a rapid and superposition-free comparison between possible binding surfaces.

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