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Frustration-driven allosteric regulation and signal transmission in the SARS-CoV-2 spike omicron trimer structures: a crosstalk of the omicron mutation sites allosterically regulates tradeoffs of protein stability and conformational adaptability.
Verkhivker, Gennady M; Agajanian, Steve; Kassab, Ryan; Krishnan, Keerthi.
  • Verkhivker GM; Keck Center for Science and Engineering, Schmid College of Science and Technology, Chapman University, Orange, CA 92866, USA.
  • Agajanian S; Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA 92618, USA.
  • Kassab R; Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. verkhivk@chapman.edu.
  • Krishnan K; Keck Center for Science and Engineering, Schmid College of Science and Technology, Chapman University, Orange, CA 92866, USA.
Phys Chem Chem Phys ; 24(29): 17723-17743, 2022 Jul 27.
Article in English | MEDLINE | ID: covidwho-1947641
ABSTRACT
Dissecting the regulatory principles underlying function and activity of the SARS-CoV-2 spike protein at the atomic level is of paramount importance for understanding the mechanisms of virus transmissibility and immune escape. In this work, we introduce a hierarchical computational approach for atomistic modeling of allosteric mechanisms in the SARS-CoV-2 Omicron spike proteins and present evidence of a frustration-based allostery as an important energetic driver of the conformational changes and spike activation. By examining conformational landscapes and the residue interaction networks in the SARS-CoV-2 Omicron spike protein structures, we have shown that the Omicron mutational sites are dynamically coupled and form a central engine of the allosterically regulated spike machinery that regulates the balance and tradeoffs between conformational plasticity, protein stability, and functional adaptability. We have found that the Omicron mutational sites at the inter-protomer regions form regulatory hotspot clusters that control functional transitions between the closed and open states. Through perturbation-based modeling of allosteric interaction networks and diffusion analysis of communications in the closed and open spike states, we have quantified the allosterically regulated activation mechanism and uncover specific regulatory roles of the Omicron mutations. Atomistic reconstruction of allosteric communication pathways and kinetic modeling using Markov transient analysis reveal that the Omicron mutations form the inter-protomer electrostatic bridges that operate as a network of coupled regulatory switches that could control global conformational changes and signal transmission in the spike protein. The results of this study have revealed distinct and yet complementary roles of the Omicron mutation sites as a network of hotspots that enable allosteric modulation of structural stability and conformational changes which are central for spike activation and virus transmissibility.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Spike Glycoprotein, Coronavirus / COVID-19 Topics: Variants Limits: Humans Language: English Journal: Phys Chem Chem Phys Journal subject: Biophysics / Chemistry Year: 2022 Document Type: Article Affiliation country: D2cp01893d

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Spike Glycoprotein, Coronavirus / COVID-19 Topics: Variants Limits: Humans Language: English Journal: Phys Chem Chem Phys Journal subject: Biophysics / Chemistry Year: 2022 Document Type: Article Affiliation country: D2cp01893d