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تسجيل مستخدم جديدHydrophobic interaction determines docking affinity of SARS CoV 2 variants with antibodies
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Preliminary epidemiologic, phylogenetic and clinical findings suggest that several novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have increased transmissibility and decreased efficacy of several existing vaccines. Four mutations in the receptor-binding domain (RBD) of the spike protein that are reported to contribute to increased transmission. Understanding physical mechanism responsible for the affinity enhancement between the SARS-CoV-2 variants and ACE2 is the urgent challenge for developing blockers, vaccines and therapeutic antibodies against the coronavirus disease 2019 (COVID-19) pandemic. Based on a hydrophobic-interaction-based protein docking mechanism, this study reveals that the mutation N501Y obviously increased the hydrophobic attraction and decrease hydrophilic repulsion between the RBD and ACE2 that most likely caused the transmissibility increment of the variants. By analyzing the mutation-induced hydrophobic surface changes in the attraction and repulsion at the binding site of the complexes of the SARS-CoV-2 variants and antibodies, we found out that all the mutations of N501Y, E484K, K417N and L452R can selectively decrease or increase their binding affinity with some antibodies.
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A recent experimental study found that the binding affinity between the cellular receptor human angiotensin converting enzyme 2 (ACE2) and receptor-binding domain (RBD) in spike (S) protein of novel severe acute respiratory syndrome coronavirus 2 (SA
RS-CoV-2) is more than 10-fold higher than that of the original severe acute respiratory syndrome coronavirus (SARS-CoV). However, main-chain structures of the SARS-CoV-2 RBD are almost the same with that of the SARS-CoV RBD. Understanding physical mechanism responsible for the outstanding affinity between the SARS-CoV-2 S and ACE2 is the urgent challenge for developing blockers, vaccines and therapeutic antibodies against the coronavirus disease 2019 (COVID-19) pandemic. Considering the mechanisms of hydrophobic interaction, hydration shell, surface tension, and the shielding effect of water molecules, this study reveals a hydrophobic-interaction-based mechanism by means of which SARS-CoV-2 S and ACE2 bind together in an aqueous environment. The hydrophobic interaction between the SARS-CoV-2 S and ACE2 protein is found to be significantly greater than that between SARS-CoV S and ACE2. At the docking site, the hydrophobic portions of the hydrophilic side chains of SARS-CoV-2 S are found to be involved in the hydrophobic interaction between SARS-CoV-2 S and ACE2. We propose a method to design live attenuated viruses by mutating several key amino acid residues of the spike protein to decrease the hydrophobic surface areas at the docking site. Mutation of a small amount of residues can greatly reduce the hydrophobic binding of the coronavirus to the receptor, which may be significant reduce infectivity and transmissibility of the virus.
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