SARS-CoV-2 Variants, RBD Mutations, Binding Affinity, and Antibody Escape

Abstract

Since 2020, the receptor-binding domain (RBD) of the spike protein of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been constantly mutating, producing most of the notable missense mutations in the context of “variants of concern”, probably in response to the vaccine-driven alteration of immune profiles of the human population. The Delta variant, in particular, has become the most prevalent variant of the epidemic, and it is spreading in countries with the highest vaccination rates, causing the world to face the risk of a new wave of the contagion. Understanding the physical mechanism responsible for the mutation-induced changes in the RBD’s binding affinity, its transmissibility, and its capacity to escape vaccine-induced immunity is the “urgent challenge” in the development of preventive measures, vaccines, and therapeutic antibodies against the coronavirus disease 2019 (COVID-19) pandemic. In this study, entropy–enthalpy compensation and the Gibbs free energy change were used to analyze the impact of the RBD mutations on the binding affinity of SARS-CoV-2 variants with the receptor angiotensin converting enzyme 2 (ACE2) and existing antibodies. Through the analysis, we found that the existing mutations have already covered almost all possible detrimental mutations that could result in an increase of transmissibility, and that a possible mutation in amino-acid position 498 of the RBD can potentially enhance its binding affinity. A new calculation method for the binding energies of protein–protein complexes is proposed based on the entropy–enthalpy compensation rule. All known structures of RBD–antibody complexes and the RBD–ACE2 complex comply with the entropy–enthalpy compensation rule in providing the driving force behind the spontaneous protein–protein docking. The variant-induced risk of breakthrough infections in vaccinated people is attributed to the L452R mutation’s reduction of the binding affinity of many antibodies. Mutations reversing the hydrophobic or hydrophilic performance of residues in the spike RBD potentially cause breakthrough infections of coronaviruses due to the changes in geometric complementarity in the entropy–enthalpy compensations between antibodies and the virus at the binding sites.

Sensitivity of SARS-CoV-2 Life Cycle to IFN Effects and ACE2 Binding Unveiled with a Stochastic Model

“…It has been shown recently that the evolution of SARS-CoV-2 results in an emergence of viral variants of concern with the enhanced transmissibility and virulence [8]. Some mutations directly affect the affinity of the virus spike protein to the ACE2 receptor [12,15].…”

“…Since the beginning of the SARS-CoV-2 pandemic, a number of new SARS-CoV-2 variants have emerged, such as the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and more recently Omicron (B.1.1.529) [8][9][10][11]. However, it is not clear how the observed specific mutations increase the transmissibility and virulence of the virus [12].…”

Immunomodulatory Role of Microelements in COVID-19 Outcome: a Relationship with Nutritional Status

“…So far, many SARS-CoV-2 mutant strains or variants have been reported and mutations located at RBD-ACE2 are associated with loss efficacy of vaccines and neutralizing antibodies [ 15 , 16 ]. These strains are classified as variants of concern (VOCs) [ 17 ], as the N501Y mutation present in variants from the UK (Alfa), South Africa (Beta), and Brazil (Gamma) that has shown an increase in ACE2 affinity causing enhanced infectivity and more severe COVID-19 [ 8 , 18 ] .…”

High-Integrity Sequencing of Spike Gene for SARS-CoV-2 Variant Determination

“…Cases and hospitalizations have continued to increase, and to date, more than 63% of the world population has received at least one dose of a COVID-19 vaccine [ 2 , 3 ]. The inherent property of viruses to achieve immune escape has induced numerous mutations in the spike protein of SARS-CoV-2, which is responsible for virus–cell binding and is the target for virus-neutralising antibodies [ 4 , 5 , 6 , 7 ]. Many vaccines are designed to generate antibodies against the spike protein [ 4 , 5 , 6 , 7 ].…”

“…The inherent property of viruses to achieve immune escape has induced numerous mutations in the spike protein of SARS-CoV-2, which is responsible for virus–cell binding and is the target for virus-neutralising antibodies [ 4 , 5 , 6 , 7 ]. Many vaccines are designed to generate antibodies against the spike protein [ 4 , 5 , 6 , 7 ]. Recently, five SARS-CoV-2 lineages were selected as variants of concern by the World Health Organization; these lineages have the following pronounced mutations in the spike protein: HVdel69-70, Ydel144, N501Y, A570D, D614G, P681H, T716I, S982A, and D1118H [ 8 ] of B.1.1.7 (Alpha); L18F, D80A, D215G, LALdel242-244, R246I, K417N, E484K, N501Y, D614G, and A701V [ 5 , 9 ] of B.1.351 (Beta); L18F, T20N, P26S, D138Y, R190S, K417N, E484K, N501Y, D614G, H655Y, and T1027I [ 10 ] of P.1 (Gamma); and T19R, K77R, G142D, EFdel156-157, R158G, A222V, L452R, T478K, D614G, P681R, and D950N [ 11 ] of B.1.617.2 (Delta); the Omicron variant is exceptional for carrying over 30 mutations in the spike glycoprotein [ 12 ].…”