An Electrostatically-steered Conformational Selection Mechanism Promotes SARS-CoV-2 Spike Protein Variation

• Published in: Journal of molecular biology 2022-07, Vol.434 (13), p.167637-167637, Article 167637
• Main Authors: Sorokina, Marija, Belapure, Jaydeep, Tüting, Christian, Paschke, Reinhard, Papasotiriou, Ioannis, Rodrigues, João P.G.L.M., Kastritis, Panagiotis L.
• Format: Article
• Language: English
• Subjects: ACE2; Angiotensin-Converting Enzyme 2; COVID-19; COVID-19 - epidemiology; HADDOCK; Humans; Pandemics - prevention & control; Protein Binding; protein–protein interactions; S protein; SARS-CoV-2 - genetics; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - genetics
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2022.167637

[Display omitted] •Analysis of S protein structural states delineates vaccine-unhindered adaptation.•We identified three strictly conserved S2 regions, critical for drug design.•Frequent substitutions increase overall hydrophobicity replacing charged amino acids.•Decreased electrostatics of frequent S protein substitutions promote RBD opening.•Understanding S protein adaptation facilitates anti-SARS-CoV-2 drug development. After two years since the outbreak, the COVID-19 pandemic remains a global public health emergency. SARS-CoV-2 variants with substitutions on the spike (S) protein emerge increasing the risk of immune evasion and cross-species transmission. Here, we analyzed the evolution of the S protein as recorded in 276,712 samples collected before the start of vaccination efforts. Our analysis shows that most variants destabilize the S protein trimer, increase its conformational heterogeneity and improve the odds of the recognition by the host cell receptor. Most frequent substitutions promote overall hydrophobicity by replacing charged amino acids, reducing stabilizing local interactions in the unbound S protein trimer. Moreover, our results identify “forbidden” regions that rarely show any sequence variation, and which are related to conformational changes occurring upon fusion. These results are significant for understanding the structure and function of SARS-CoV-2 related proteins which is a critical step in vaccine development and epidemiological surveillance.