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.
Highlights
The coronavirus disease 2019 (COVID-19) has spread worldwide, with more than 230 million confirmed cases, and has led to an ongoing pandemic
If the binding energies of the Ho-Ho, Ho-Hi, attractive dipole–dipole (ADD), and repulsive dipole–dipole (RDD) interactions among surface areas can be separately calculated, the binging energies of protein–protein complexes can be calculated based on the entropy–enthalpy compensation rule
Experimental results show that water molecules slow down greatly when they encounter the hydrophobic areas of a protein, and the speed is reduced by 99% [33]
Summary
The coronavirus disease 2019 (COVID-19) has spread worldwide, with more than 230 million confirmed cases, and has led to an ongoing pandemic. In response to this once-in-a-century, sustained, worldwide pandemic, unprecedented amounts of funds and manpower have been invested to develop vaccines against the disease by governments, corporations, university research groups, and international health organizations [1]. By. September 2020, about 20 countries had vaccinated over 70% of their populations, and the best vaccination rates in the world are dominated by small countries. The original SARS-CoV-2 strain is disappearing in countries with the best vaccination rates. The SARS-CoV-2 variants have almost replaced the initial
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