Evolution of the SARS‐CoV‐2 proteome in three dimensions (3D) during the first 6 months of the COVID‐19 pandemic

Abstract

Understanding the molecular evolution of the SARS‐CoV‐2 virus as it continues to spread in communities around the globe is important for mitigation and future pandemic preparedness. Three‐dimensional structures of SARS‐CoV‐2 proteins and those of other coronavirusess archived in the Protein Data Bank were used to analyze viral proteome evolution during the first 6 months of the COVID‐19 pandemic. Analyses of spatial locations, chemical properties, and structural and energetic impacts of the observed amino acid changes in >48 000 viral isolates revealed how each one of 29 viral proteins have undergone amino acid changes. Catalytic residues in active sites and binding residues in protein–protein interfaces showed modest, but significant, numbers of substitutions, highlighting the mutational robustness of the viral proteome. Energetics calculations showed that the impact of substitutions on the thermodynamic stability of the proteome follows a universal bi‐Gaussian distribution. Detailed results are presented for potential drug discovery targets and the four structural proteins that comprise the virion, highlighting substitutions with the potential to impact protein structure, enzyme activity, and protein–protein and protein–nucleic acid interfaces. Characterizing the evolution of the virus in three dimensions provides testable insights into viral protein function and should aid in structure‐based drug discovery efforts as well as the prospective identification of amino acid substitutions with potential for drug resistance.

Structural models of SARS-CoV-2 Omicron variant in complex with ACE2 receptor or antibodies suggest altered binding interfaces

“…We have previously developed an “ in silico mutagenesis” and analysis pipeline for studying the ongoing populational co-evolution of SARS-CoV-2. 14 In our pipeline, amino acid substitutions observed in sequenced SARS-CoV-2 genomes obtained from the GISAID database 15,16 are introduced in available crystal structures or computed structural models of proteins and their energetic impact is qualitatively evaluated. We have previously focused on evaluating how observed mutations affect the structure and stability of individual proteins and domains for SARS-CoV-2.…”

“…We have previously focused on evaluating how observed mutations affect the structure and stability of individual proteins and domains for SARS-CoV-2. 14 We adapted this pipeline ( Fig. 1C ) to the evaluation of omRBD in complex with ACE2 and bound antibodies, etc.…”

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

“… Genomics organization and proteins of SARS-CoV-2. Adapted with permission from ref ( 13 ). Copyright 2021 John Wiley and Sons.…”

Characteristics of the SARS-CoV-2 Omicron (B.1.1.529) Variant and Emerging Impact on Global Public Health

“… 29 The massive quantity of residue mutations observed in the spike protein (herein after spike) (~30) distinguishes this VOC from all previously reported COVID19 strains, the possible changes occurred in many (~15) receptor-binding domain (RBD) of its spike protein. 30 As a result, they may either reduce or escape the immunological responses elicited by vaccination and/or past natural infection in individuals ( Figure 1 ). If the Omicron variant spreads wildly and very rapidly as a dominant variant strain over the world, immune escape or evasion could have serious consequences, such as higher infection rates, reinfection, and/or an increase in the evolution of viral fitness.…”