MOLECULAR DOCKING DEPICTS ANCHORING OF THE SECOND ARGININE FROM THE POLYBASIC CLEAVAGE MOTIF IN SARS-COV-2 SPIKE PROTEIN TO HUMAN TMPRSS2 BUT UNFAVORED TO OTHER MAMMALS ORTHOLOGS

Arthur Pereira da Fonseca; Lucianna Helene Silva dos Santos; Lucas Bleicher; J. Miguel Ortega

Paper Title

Authors

Arthur Pereira da Fonseca
Lucianna Helene Silva dos Santos
Lucas Bleicher
J. Miguel Ortega

Modality

Xpress presentation

Subject area

Structural Bioinformatics

Publishing Date

26/04/2022

Country of Publishing

Brasil

Language of Publishing

Inglês

Paper Page

https://www.even3.com.br/anais/xmeetingxp2021/422346-molecular-docking-depicts-anchoring-of-the-second-arginine-from-the-polybasic-cleavage-motif-in-sars-cov-2-spike-

ISBN

978-65-5941-645-5

Keywords

Coronavirus, Covid, SARS-CoV-2, TMPRSS2, TMPRSS2 orthologues

Summary

SARS-CoV-2 acquired a polybasic motif in Spike protein, composing the amino acid sequence PRRAR, which is believed to have adapted the virus to the human host, making it susceptible to our serino proteases catalytic action. We set out to study the phylogenetic distribution of the transmembrane serine protease 2 (TMPRSS2) pointed out to cleave this polybasic motif, which plays a key role for virus recognition and cell entry via human cell receptor ACE2. We found that a clade containing primate proteins has a near clade in carnivores, including cat, followed by a murine clade and by a less related clade containing bovine. To investigate the enzyme affinity for the acquired motif in the different orthologs, we searched the coronavirus spike protein loop bearing the putative cleavage site and prepared it in pdb format, then we conducted a molecular docking of this peptide to each one of the orthologs enzymes using CABSdock software. To confirm the binding stability, a 150 nanoseconds dynamics simulation of the docked complex was run with NAMD. We observed at the final 10 ns of simulation, the association of the second arginine in the PRRAR motif (Arg683 in spike protein) with the human TMPRSS2, presenting average distance to the enzyme residues Trp461, His296, Asp345 and Ser441 of, respectively, 4.3, 7.4, 4.8 and 6.6 Angstroms. Conversely, the respective distances for the orthologue enzymes were 16.6, 12.2, 10.7 and 18.8 Angstroms for cat and 10.9, 16.2, 11.7 and 22.3 Angstroms for mouse. In bovine the Arginine lateral chain in peptide was close to two of the enzyme positions: Trp 4.2 and His 4.6 Angstroms, although distant from Ser 7.0 and Asp 11.2 Angstroms. Thus, our data suggests that the recognition of the mentioned Arginine may be of importance for substrate binding and subsequent cleavage by TMPRSS2 and activation of the Spike protein to increase its binding to ACE2 receptor, and that this detail might be related to a specific highly efficient cleavage by the human enzyme as compared to the other mammals orthologues.

Title of the Event: X-Meeting XPerience 2021
Title of the Proceedings of the event: X-Meeting presentations
Name of the Publisher: Even3
Means of Dissemination: Meio Digital

How to cite

FONSECA, Arthur Pereira da et al.. MOLECULAR DOCKING DEPICTS ANCHORING OF THE SECOND ARGININE FROM THE POLYBASIC CLEAVAGE MOTIF IN SARS-COV-2 SPIKE PROTEIN TO HUMAN TMPRSS2 BUT UNFAVORED TO OTHER MAMMALS ORTHOLOGS.. In: X-Meeting presentations. Anais...São Paulo(SP) AB3C, 2021. Available in: https//www.even3.com.br/anais/xmeetingxp2021/422346-MOLECULAR-DOCKING-DEPICTS-ANCHORING-OF-THE-SECOND-ARGININE-FROM-THE-POLYBASIC-CLEAVAGE-MOTIF-IN-SARS-COV-2-SPIKE-. Access in: 29/05/2025