SARS-CoV-2 variants impact RBD conformational dynamics and ACE2 accessibility

Mariana Valério; Luís Borges-Araújo; Manuel N Melo; Diana Lousa; Cláudio M Soares

doi:10.3389/fmedt.2022.1009451

SARS-CoV-2 variants impact RBD conformational dynamics and ACE2 accessibility

Front Med Technol. 2022 Oct 5:4:1009451. doi: 10.3389/fmedt.2022.1009451. eCollection 2022.

Authors

Mariana Valério^{1

2}, Luís Borges-Araújo^{1

2

3

4}, Manuel N Melo^{1

2}, Diana Lousa^{1

2}, Cláudio M Soares^{1

2}

Affiliations

¹ Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal.
² Associated Laboratory LS4FUTURE, ITQB NOVA, Universidade Nova de Lisboa, Oeiras, Portugal.
³ iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.
⁴ Associate Laboratory i4HB-Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.

Abstract

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed over 6 million people and is having a devastating social and economic impact around the world. The rise of new variants of concern (VOCs) represents a difficult challenge due to the loss of vaccine and natural immunity, as well as increased transmissibility. All VOCs contain mutations in the spike glycoprotein, which mediates fusion between the viral and host cell membranes. The spike glycoprotein binds to angiotensin-converting enzyme 2 (ACE2) via its receptor binding domain (RBD) initiating the infection process. Attempting to understand the effect of RBD mutations in VOCs, a lot of attention has been given to the RBD-ACE2 interaction. However, this type of analysis ignores more indirect effects, such as the conformational dynamics of the RBD itself. Observing that some mutations occur in residues that are not in direct contact with ACE2, we hypothesized that they could affect the RBD conformational dynamics. To test this, we performed long atomistic (AA) molecular dynamics (MD) simulations to investigate the structural dynamics of wt RBD, and that of four VOCs (Alpha, Beta, Delta, and Omicron). Our results show that the wt RBD presents two distinct conformations: an "open" conformation where it is free to bind ACE2; and a "closed" conformation, where the RBM ridge blocks the binding surface. The Alpha and Beta variants shift the open/closed equilibrium towards the open conformation by roughly 20%, likely increasing ACE2 binding affinity. Simulations of the Delta and Omicron variants showed extreme results, with the closed conformation being rarely observed. The Delta variant also differed substantially from the other variants, alternating between the open conformation and an alternative "reversed" one, with a significantly changed orientation of the RBM ridge. This alternate conformation could provide a fitness advantage due to increased availability for ACE2 binding, and by aiding antibody escape through epitope occlusion. These results support the hypothesis that VOCs, and particularly the Omicron and Delta variants, impact RBD conformational dynamics in a direction that promotes efficient binding to ACE2 and, in the case of Delta, may assist antibody escape.

Keywords: MD simulations; SARS-CoV-2; receptor binding domain (RBD); ridge; variants of concern (VOCs).