Systemic effects of missense mutations on SARS-CoV-2 spike glycoprotein stability and receptor-binding affinity

Abstract

The spike (S) glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the binding to the permissive cells. The receptor-binding domain (RBD) of SARS-CoV-2 S protein directly interacts with the human angiotensin-converting enzyme 2 (ACE2) on the host cell membrane. In this study, we used computational saturation mutagenesis approaches, including structure-based energy calculations and sequence-based pathogenicity predictions, to quantify the systemic effects of missense mutations on SARS-CoV-2 S protein structure and function. A total of 18 354 mutations in S protein were analyzed, and we discovered that most of these mutations could destabilize the entire S protein and its RBD. Specifically, residues G431 and S514 in SARS-CoV-2 RBD are important for S protein stability. We analyzed 384 experimentally verified S missense variations and revealed that the dominant pandemic form, D614G, can stabilize the entire S protein. Moreover, many mutations in N-linked glycosylation sites can increase the stability of the S protein. In addition, we investigated 3705 mutations in SARS-CoV-2 RBD and 11 324 mutations in human ACE2 and found that SARS-CoV-2 neighbor residues G496 and F497 and ACE2 residues D355 and Y41 are critical for the RBD–ACE2 interaction. The findings comprehensively provide potential target sites in the development of drugs and vaccines against COVID-19.

Transmission, infectivity, and neutralization of a spike L452R SARS-CoV-2 variant

“…Prior studies have suggested that the L452R mutation may stabilize the interaction between the spike protein and its human ACE2 receptor and thereby increase infectivity (Chen et al, 2020;Teng et al, 2021). Our findings of enhanced infection of 293T cells and lung organoids by pseudoviruses carrying L452R confirm these early predictions.…”

SARS-CoV-2 Genomic Surveillance in Costa Rica: Evidence of a Divergent Population and an Increased Detection of a Spike T1117I Mutation

“…Despite the relation between D614G and transmissibility, severity or mortality remains unclear (Grubaugh et al, 2020), different studies have suggested different implications in transmission and immune response (Teng et al, 2020;Zhang et al, 2020), but analytical and epidemiological factors could explain this observation. In patients, D614G has been associated with higher viral loads, but without significant changes of the disease severity (Korber et al, 2020;Plante et al, 2020) or vaccine effectiveness (Plante et al, 2020;Zhang et al, 2020).…”

“…Although strong relationships between specific variants or clades in SARS-CoV-2 and the clinical outcome have not been identified (Grubaugh, Hanage, & Rasmussen, 2020;Hodcroft et al, 2020;van Dorp et al, 2020), different relevant parameters could be impacted by mutations in the virus genome. These include transmissibility, severity, clinical management, mortality, vaccines as well as the performance of molecular tests for diagnosis (Hodcroft et al, 2020;Koyama, Platt, & Parida, 2020;Teng, Sobitan, Rhoades, Liu, & Tang, 2020). Until now, genetic factors and, more importantly, comorbidities of the host seem to have the predominant impact on the fate of COVID-19 patients (LoPresti, Beck, Duggal, Cummings, & Solomon, 2020;Sironi et al, 2020;Toyoshima, Nemoto, Matsumoto, Nakamura, & Kiyotani, 2020).…”

Evolutionary analysis of SARS‐CoV‐2 spike protein for its different clades

“…were associated with the binding affinity of RBD. 30,31 Additionally, the mutation L5F in the signal peptide was present in 3.3% of members belonging clade V. 27 Other changes associated to relevant functions 27,30 The evolutionary rate of S protein estimated for all together clades was significantly higher than that previously reported by analyzing the entire genome. 14,28 This is expected as the complete…”