S494 O-glycosylation site on the SARS-CoV-2 RBD affects the virus affinity to ACE2 and its infectivity; a molecular dynamics study

Shadi Rahnama,Mohammad Reza Ejtehadi,Mehriar Amininasab,Maryam Azimzadeh Irani

doi:10.1038/s41598-021-94602-w

Shadi Rahnama, Mohammad Reza Ejtehadi + Show 2 more

Open Access

https://doi.org/10.1038/s41598-021-94602-w

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Abstract

SARS-CoV-2 is a strain of Coronavirus family that caused the ongoing pandemic of COVID-19. Several studies showed that the glycosylation of virus spike (S) protein and the Angiotensin-Converting Enzyme 2 (ACE2) receptor on the host cell is critical for the virus infectivity. Molecular Dynamics (MD) simulations were used to explore the role of a novel mutated O-glycosylation site (D494S) on the Receptor Binding Domain (RBD) of S protein. This site was suggested as a key mediator of virus-host interaction. By exploring the dynamics of three O-glycosylated models and the control systems of unglcosylated S4944 and S494D complexes, it was shown that the decoration of S494 with elongated O-glycans results in stabilized interactions on the direct RBD-ACE2. Calculation of the distances between RBD and two major H1, H2 helices of ACE2 and the interacting pairs of amino acids in the interface showed that the elongated O-glycan maintains these interactions by forming several polar contacts with the neighbouring residues while it would not interfere in the direct binding interface. Relative binding free energy of RBD-ACE2 is also more favorable in the O-glycosylated models with longer glycans. The increase of RBD binding affinity to ACE2 depends on the size of attached O-glycan. By increasing the size of O-glycan, the RBD-ACE2 binding affinity will increase. Hence, this crucial factor must be taken into account for any further inhibitory approaches towards RBD-ACE2 interaction.

Highlights

SARS-CoV-2 is a strain of Coronavirus family that caused the ongoing pandemic of COVID-19
The fusion protein known as the spike (S) protein interacts with Angiotensin-Converting Enzyme 2 (ACE2) on the host cell via its Receptor Binding Domain (RBD)[3,9] (Fig. 1).The RBD-ACE2 interaction takes place via four β strands on RBD (β4–β7) and two α helices on ACE2 binding interface (H1,H2)[3] (Fig. 1)
S494 that only occurs in SARS-CoV-2 and not in SARS-CoV is located in direct RBD-ACE2 binding interface has the potential to be decorated by O-glycans

Summary

Introduction

SARS-CoV-2 is a strain of Coronavirus family that caused the ongoing pandemic of COVID-19. Molecular Dynamics (MD) simulations were used to explore the role of a novel mutated O-glycosylation site (D494S) on the Receptor Binding Domain (RBD) of S protein. This site was suggested as a key mediator of virus-host interaction. By exploring the dynamics of three O-glycosylated models and the control systems of unglcosylated S4944 and S494D complexes, it was shown that the decoration of S494 with elongated O-glycans results in stabilized interactions on the direct RBD-ACE2. The mutations in SARS-CoV-2 RBD certainly results in attenuated binding affinity of all designed inhibitors which successfully work on SARS-CoV2. Earlier MD studies explored the effect of pH13 and temperature[14] on the dynamics of SARS-CoV-ACE2 complex.To the best of our knowledge, there is currently no approved therapeutic inhibitor for SARS-CoV-2

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