Studying On The Binding Mechanism Of SARS-CoV-2 Variants To ACE2 And Antiviral Molecules Based On Interaction Entropy Method

Corona Virus Disease 2019(COVID-19),caused by Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2),has caused millions of deaths worldwide and poses a major threat to public health and socio-economic development.SARS-CoV-2 belongs to the β genus single-stranded RNA viruses,and its surface transmembrane spike glycoprotein can specifically recognize the host cell receptor angiotensin-converting enzyme2(ACE2)through the receptor-binding domain(RBD)to mediate virus invasion.This process has been identified as a critical step of viral infection in the body,and the RBD has also become a significant target for drug and antibody research.However,the high mutability of RNA viruses has led to persistent mutations of SARS-CoV-2 in recent years,with some variants showing increased virulence and infectivity,and even immune escape against existing antibodies,posing a great challenge to outbreak control and the development of antiviral strategies.Therefore,it is meaningful to research the binding process of current prevalent variants to ACE2 and existing antiviral molecules,this will provide novel insights into the development of drugs and antibodies against novel variants.Three areas of research have been undertaken in this paper around this issue:This study investigated the molecular mechanism underlying the strong infectivity of the SARS-CoV-2 Delta variant by combining molecular dynamics simulation with alanine scanning and interaction entropy(IE)methods.Both energetic and conformational results show that the introduction of positively charged amino acids(Arg and Lys)by two mutation sites(L452R and T478K)contained in the Delta variant RBD significantly enhances the electrostatic interaction energy between RBD and ACE2.At the same time,several conformations of the receptor binding motif(RBM)of the Delta variant,dominated by the T478 K mutation,contract and form a tighter binding to ACE2.In addition,these conformational changes result in a more stable hydrogen bond in the Delta variant,further ensuring binding stability.Subsequently,multiple-site mutated SARS-CoV-2 Delta and Omicron variants may trigger immune escape against existing monoclonal antibodies.Here,molecular dynamics simulation combined with the interaction entropy method reveal the escape mechanism of Delta and Omicron variants to Bamlanivimab and Etesevimab.The result shows the significantly reduced binding affinity of the Omicron variant for both antibodies,due to the introduction of positively charged residues that greatly weaken their electrostatic interactions.Meanwhile,significant structural deflection induces fewer atomic contacts and an unstable binding mode.As for the Delta variant,the reduced binding affinity for Bamlanivimab is owing to the alienation of the receptor-binding domain to the main part of this antibody,and the binding mode of the Delta variant to Etesevimab is similar to that of the wild type,suggesting that Etesevimab could still be effective against the Delta variant.In addition,convenient and efficient therapeutic agents are urgently needed to block the continued spread of SARS-CoV-2.Here,the mechanism for the novel orally targeted SARS-CoV-2 main protease(Mpro)inhibitor S-217622 is revealed through a molecular dynamics simulation.The difference in the movement modes of the S-217622/Mpro complex and apo-Mpro suggested S-217622 could inhibit the motility intensity of Mpro,thus maintaining their stable binding.Subsequent energy calculations showed that the P2 pharmacophore possessed the highest energy contribution among the three pharmacophores of S-217622.Additionally,hot-spot residues H41,M165,C145,E166,and H163 have strong interactions with S-217622.To further investigate the resistance of S-217622 to six mainstream variants,the binding modes of S-217622 with these variants were elucidated.The subtle differences in energy compared to that of the wild type implied that the binding patterns of these systems were similar,and S-217622 still inhibited these variants.These analyses and results will provide timely theoretical insights for drug and antibody development against existing or potentially future prevalent SARS-CoV-2 variants.