Binding affinity improvement analysis of multiple-mutant Omicron on 2019-nCov to human ACE2 by in silico predictions

Abstract

ContextSince the outbreak of COVID-19 in 2019, the 2019-nCovcoronavirus has appeared diverse mutational characteristics due to its ownflexible conformation. One multiple-mutant strain (Omicron) with surprisinglyinfective activity outburst, and affected the biological activities of currentdrugs and vaccines, making the epidemic significantly difficult to prevent andcontrol, and seriously threaten health around the world. Importunatelyexploration of mutant characteristics for novel coronavirus Omicron can supplystrong theoretical guidance for learning binding mechanism of mutant viruses.What’s more, full acknowledgement of key mutated-residues on Omicron strain canprovide new methodology of the novel pathogenic mechanism to human ACE2receptor, as well as the subsequent vaccine development.MethodsIn this research, 3D structures of 32 single-point mutationsof 2019-nCov were firstly constructed, and 32-sites multiple-mutant Omicronwere finally obtained based one the wild-type virus by homology modeling method.One total number of 33 2019-nCov/ACE2 complex systems were acquired byprotein-protein docking, and optimized by using preliminary molecular dynamicsimulations. Binding free energies between each 2019-nCov mutation system andhuman ACE2 receptor were calculated, and corresponding binding patternsespecially the regions adjacent to mutation site were analyzed. The resultsindicated that one total number of 6 mutated sites on the Omicron strain playedcrucial role in improving binding capacities from 2019-nCov to ACE2 protein.Subsequently, we performed long-term molecular dynamic simulations andprotein-protein binding energy analysis for the selected 6 mutations. 3infected individuals, the mutants T478K, Q493R and G496S with lower bindingenergies -66.36, -67.98 and -67.09 kcal/mol also presents the high infectivity.These findings indicated that the 3 mutations T478K, Q493R and G496S play thecrucial roles in enhancing binding affinity of Omicron to human ACE2 protein.All these results illuminate important theoretical guidance for future virusdetection of the Omicron epidemic, drug research and vaccine development.