bioRxiv preprint doi: https://doi.org/10.1101/2021.08.12.456168; this version posted August 13, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. SARS-CoV-2 spike opening dynamics and energetics reveal the individual roles of glycans and their collective impact Yui Tik Pang,y,z Atanu Acharya,y,z Diane L. Lynch,y Anna Pavlova,y and James C. Gumbart∗,y ySchool of Physics, Georgia Institute of Technology, Atlanta, GA 30332 zContributed equally to this work E-mail:
[email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.08.12.456168; this version posted August 13, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract The trimeric spike (S) glycoprotein, which protrudes from the SARS-CoV-2 viral envelope, is responsible for binding to human ACE2 receptors. The binding process is initiated when the receptor binding domain (RBD) of at least one protomer switches from a “down” (closed) to an “up” (open) state. Here, we used molecular dynamics simulations and two-dimensional replica exchange umbrella sampling calculations to investigate the transition between the two S-protein conformations with and without glycosylation. We show that the glycosylated spike has a higher barrier to opening than the non-glycosylated one with comparable populations of the down and up states. In contrast, we observed that the up conformation is favored without glycans.