Mechanistic insights into ligand dissociation from the SARS-CoV-2 spike glycoprotein

• DOI: 10.1101/2023.11.29.569184
• Publication Date: 2023-12-01T02:35:14Z
• Authors: Timothy Hasse; Esra Mantei; Rezvan Shahoei; Shristi Pawnikar; Jinan Wang; Yinglong Miao; Yu-ming M. Huang
• Keywords: QH301-705.5; Biology (General); Research Article

Abstract The COVID-19 pandemic, driven by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spurred an urgent need for effective therapeutic interventions. spike glycoprotein of SARS-CoV-2 is crucial infiltrating host cells, rendering it a key candidate drug development. By interacting with human angiotensin-converting enzyme (ACE2) receptor, initiates infection SARS-CoV-2. Linoleate known to bind glycoprotein, subsequently reducing its interaction ACE2. However, detailed kinetics underlying protein-ligand remains unclear. In this study, we characterized pathways ligand dissociation and conformational changes associated using Gaussian accelerated molecular dynamics (LiGaMD). Our simulations resulted in eight complete trajectories, unveiling two distinct unbinding pathways. preference between these depends on gate distance α-helices receptor binding domain (RBD) position N-linked glycan at N343. study also highlights essential contributions K417, N121 glycan, N165 unbinding, which are equally enhancing spike-ACE2 binding. We suggest that presence influences motions residues glycans, consequently accessibility These findings enhance our understanding from offer significant implications design strategies battle against COVID-19.