Structures and dynamics of the novel S1/S2 protease cleavage site loop of the SARS-CoV-2 spike glycoprotein

Thomas Lemmin; David Kalbermatter; Daniel Harder; Philippe Plattet; Dimitrios Fotiadis

doi:10.1016/j.yjsbx.2020.100038

Structures and dynamics of the novel S1/S2 protease cleavage site loop of the SARS-CoV-2 spike glycoprotein

J Struct Biol X. 2020:4:100038. doi: 10.1016/j.yjsbx.2020.100038. Epub 2020 Oct 5.

Authors

Thomas Lemmin^{1

2}, David Kalbermatter³, Daniel Harder³, Philippe Plattet⁴, Dimitrios Fotiadis³

Affiliations

¹ DS3Lab, System Group, Department of Computer Sciences, ETH Zurich, CH-8092 Zürich, Switzerland.
² Trkola Group, Institute for Virology, University of Zurich, CH-8057 Zürich, Switzerland.
³ Institute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, CH-3012 Bern, Switzerland.
⁴ Division of Experimental and Clinical Research, Vetsuisse Faculty, University of Bern, CH-3012 Bern, Switzerland.

Abstract

At the end of 2019, a new highly virulent coronavirus known under the name SARS-CoV-2 emerged as a human pathogen. One key feature of SARS-CoV-2 is the presence of an enigmatic insertion in the spike glycoprotein gene representing a novel multibasic S1/S2 protease cleavage site. The proteolytic cleavage of the spike at this site is essential for viral entry into host cells. However, it has been systematically abrogated in structural studies in order to stabilize the spike in the prefusion state. In this study, multi-microsecond molecular dynamics simulations and ab initio modeling were leveraged to gain insights into the structures and dynamics of the loop containing the S1/S2 protease cleavage site. They unveiled distinct conformations, formations of short helices and interactions of the loop with neighboring glycans that could potentially regulate the accessibility of the cleavage site to proteases and its processing. In most conformations, this loop protrudes from the spike, thus representing an attractive SARS-CoV-2 specific therapeutic target.

Keywords: Ab initio modelling; Coronavirus; Furin cleavage site; Molecular dynamics simulation; SARS-CoV-2; Spike glycoprotein.