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

J Mol Biol

Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 06120 Halle/Saale, Germany; Interdisciplinary Research Center HALOmem, Charles Tanford Protein Center, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3a, 06120 Halle/Saale, Germany; Biozentrum, Martin Luther University Halle-Wittenberg, Weinbergweg 22, 06120 Halle/Saale, Germany. Electronic address:

Published: July 2022

AI Article Synopsis

  • The COVID-19 pandemic, two years in, still poses a global health crisis with evolving SARS-CoV-2 variants that may evade immunity and potentially transmit between species.
  • Analysis of 276,712 samples shows that these variants destabilize the spike (S) protein, making it more likely for host cells to recognize it by altering its structure and increasing its hydrophobicity.
  • Key findings highlight specific regions in the S protein that rarely change, which are crucial for understanding its function and will aid in vaccine development and monitoring disease spread.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9112565PMC
http://dx.doi.org/10.1016/j.jmb.2022.167637DOI Listing

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