What are the molecular determinants of protein-protein binding affinity and whether they are similar to those regulating fold stability are two major questions of molecular biology, whose answers bring important implications both from a theoretical and applicative point of view. Here, we analyze chemical and physical features on a large dataset of protein-protein complexes with reliable experimental binding affinity data and compare them with a set of monomeric proteins for which melting temperature data was available. In particular, we probed the spatial organization of protein (1) intramolecular and intermolecular interaction energies among residues, (2) amino acidic composition, and (3) their hydropathy features. Analyzing the interaction energies, we found that strong Coulombic interactions are preferentially associated with a high protein thermal stability, while strong intermolecular van der Waals energies correlate with stronger protein-protein binding affinity. Statistical analysis of amino acids abundances, exposed to the molecular surface and/or in interaction with the molecular partner, confirmed that hydrophobic residues present on the protein surfaces are preferentially located in the binding regions, while charged residues behave oppositely. Leveraging on the important role of van der Waals interface interactions in binding affinity, we focused on the molecular surfaces in the binding regions and evaluated their shape complementarity, decomposing the molecular patches in the 2D Zernike basis. For the first time, we quantified the correlation between local shape complementarity and binding affinity via the Zernike formalism. In addition, considering the solvent interactions via the residue hydropathy, we found that the hydrophobicity of the binding regions dictates their shape complementary as much as the correlation between van der Waals energy and binding affinity. In turn, these relationships 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.

Spatial organization of hydrophobic and charged residues affects protein thermal stability and binding affinity / Desantis, Fausta; Miotto, Mattia; DI RIENZO, Lorenzo; Milanetti, Edoardo; Ruocco, Giancarlo. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 12:1(2022). [10.1038/s41598-022-16338-5]

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

Fausta Desantis;Mattia Miotto
Conceptualization
;
Lorenzo Di Rienzo;Edoardo Milanetti;Giancarlo Ruocco
2022

Abstract

What are the molecular determinants of protein-protein binding affinity and whether they are similar to those regulating fold stability are two major questions of molecular biology, whose answers bring important implications both from a theoretical and applicative point of view. Here, we analyze chemical and physical features on a large dataset of protein-protein complexes with reliable experimental binding affinity data and compare them with a set of monomeric proteins for which melting temperature data was available. In particular, we probed the spatial organization of protein (1) intramolecular and intermolecular interaction energies among residues, (2) amino acidic composition, and (3) their hydropathy features. Analyzing the interaction energies, we found that strong Coulombic interactions are preferentially associated with a high protein thermal stability, while strong intermolecular van der Waals energies correlate with stronger protein-protein binding affinity. Statistical analysis of amino acids abundances, exposed to the molecular surface and/or in interaction with the molecular partner, confirmed that hydrophobic residues present on the protein surfaces are preferentially located in the binding regions, while charged residues behave oppositely. Leveraging on the important role of van der Waals interface interactions in binding affinity, we focused on the molecular surfaces in the binding regions and evaluated their shape complementarity, decomposing the molecular patches in the 2D Zernike basis. For the first time, we quantified the correlation between local shape complementarity and binding affinity via the Zernike formalism. In addition, considering the solvent interactions via the residue hydropathy, we found that the hydrophobicity of the binding regions dictates their shape complementary as much as the correlation between van der Waals energy and binding affinity. In turn, these relationships 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.
2022
Hydrophobic and Hydrophilic Interactions; Protein Binding; Protein Stability; Thermodynamics; Amino Acids; Membrane Proteins
01 Pubblicazione su rivista::01a Articolo in rivista
Spatial organization of hydrophobic and charged residues affects protein thermal stability and binding affinity / Desantis, Fausta; Miotto, Mattia; DI RIENZO, Lorenzo; Milanetti, Edoardo; Ruocco, Giancarlo. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 12:1(2022). [10.1038/s41598-022-16338-5]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1659901
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