Differences in the organization of interface residues tunes the stability of the SARS-CoV-2 spike-ACE2 complex

Frontiers in Molecular Biosciences

Molecular Biosciences

Lorenzo Di Rienzo¹  Mattia Miotto¹  Gianluca Cidonio¹  Greta Grassmann²  Giancarlo Ruocco³  Edoardo Milanetti³  Marco Leonetti⁴  Giorgio Gosti⁴  Fausta Desantis⁵ 

[1] Center for Life Nano-& Neuro-Science, Istituto Italiano di Tecnologia, Rome, Italy;Center for Life Nano-& Neuro-Science, Istituto Italiano di Tecnologia, Rome, Italy;Department of Biochemical Sciences “Alessandro Rossi Fanelli”, Sapienza University of Rome, Rome, Italy;Center for Life Nano-& Neuro-Science, Istituto Italiano di Tecnologia, Rome, Italy;Department of Physics, Sapienza University of Rome, Rome, Italy;Center for Life Nano-& Neuro-Science, Istituto Italiano di Tecnologia, Rome, Italy;Soft and Living Matter Laboratory, Institute of Nanotechnology, Consiglio Nazionale delle Ricerche, Rome, Italy;Center for Life Nano-& Neuro-Science, Istituto Italiano di Tecnologia, Rome, Italy;The Open University Affiliated Research Centre at Istituto Italiano di Tecnologia, Genova, Italy;

关键词: SARS-C0V-2;    complex stability;    Zernike 2D;    SARS-COV-2 variants;    energetic interactions;   

DOI  :  10.3389/fmolb.2023.1205919

 received in 2023-04-14, accepted in 2023-06-13,  发布年份 2023

来源: Frontiers

【 摘 要 】

The continuous emergence of novel variants represents one of the major problems in dealing with the SARS-CoV-2 virus. Indeed, also due to its prolonged circulation, more than ten variants of concern emerged, each time rapidly overgrowing the current viral version due to improved spreading features. As, up to now, all variants carry at least one mutation on the spike Receptor Binding Domain, the stability of the binding between the SARS-CoV-2 spike protein and the human ACE2 receptor seems one of the molecular determinants behind the viral spreading potential. In this framework, a better understanding of the interplay between spike mutations and complex stability can help to assess the impact of novel variants. Here, we characterize the peculiarities of the most representative variants of concern in terms of the molecular interactions taking place between the residues of the spike RBD and those of the ACE2 receptor. To do so, we performed molecular dynamics simulations of the RBD-ACE2 complexes of the seven variants of concern in comparison with a large set of complexes with different single mutations taking place on the RBD solvent-exposed residues and for which the experimental binding affinity was available. Analyzing the strength and spatial organization of the intermolecular interactions of the binding region residues, we found that (i) mutations producing an increase of the complex stability mainly rely on instaurating more favorable van der Waals optimization at the cost of Coulombic ones. In particular, (ii) an anti-correlation is observed between the shape and electrostatic complementarities of the binding regions. Finally, (iii) we showed that combining a set of dynamical descriptors is possible to estimate the outcome of point mutations on the complex binding region with a performance of 0.7. Overall, our results introduce a set of dynamical observables that can be rapidly evaluated to probe the effects of novel isolated variants or different molecular systems.

【 授权许可】

Unknown   
Copyright © 2023 Miotto, Di Rienzo, Grassmann, Desantis, Cidonio, Gosti, Leonetti, Ruocco and Milanetti.