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

Abstract

Since the outbreak of COVID-19 in 2019, the 2019-nCov coronavirus has appeared diverse mutational characteristics due to its own flexible conformation. One multiple-mutant strain (Omicron) with surprisingly infective activity outburst, and affected the biological activities of current drugs and vaccines, making the epidemic significantly difficult to prevent and control, and seriously threaten health around the world. Importunately exploration of mutant characteristics for novel coronavirus Omicron can supply strong theoretical guidance for learning binding mechanism of mutant viruses. What’s more, full acknowledgement of key mutated-residues on Omicron strain can provide new methodology of the novel pathogenic mechanism to human ACE2 receptor, as well as the subsequent vaccine development. In this research, 3D structures of 32 single-point mutations of 2019-nCov were firstly constructed, and 32-sites multiple-mutant Omicron were finally obtained based one the wild-type virus by homology modeling method. One total number of 33 2019-nCov/ACE2 complex systems were acquired by protein-protein docking, and optimized by using preliminary molecular dynamics simulations. Binding free energies between each 2019-nCov mutation system and human ACE2 receptor were calculated, and corresponding binding patterns especially the regions adjacent to mutation site were analyzed. The results indicated that one total number of 6 mutated sites on the Omicron strain played crucial role in improving binding capacities from 2019-nCov to ACE2 protein. Subsequently, we performed long-term molecular dynamic simulations and protein-protein binding energy analysis for the selected 6 mutations. 3 infected individuals, the mutants T478K, Q493R and G496S with lower binding energies − 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 the crucial roles in enhancing binding affinity of Omicron to human ACE2 protein. All these results illuminate important theoretical guidance for future virus detection of the Omicron epidemic, drug research and vaccine development.

Exploring the Binding Affinity and Mechanism between ACE2 and the Trimers of Delta and Omicron Spike Proteins by Molecular Dynamics Simulation and Bioassay

“…However, the dynamic analysis is mainly for RBD-ACE2 in the Omicron variant, not for St-ACE2. For example, several reports described the various interaction patterns for the WT, Delta, and Omicron RBD-ACE2 by molecular dynamics (MD) simulation. − There are only two available articles related to dynamic analysis, that is MD simulation, for the Omicron St-ACE2 system, and they concentrated on either the change of overall stability through simulation in vacuum environment or the influence of individual mutation on the interaction . However, neither of them analyzed in detail the dynamics and the comprehensive interaction network including conserved residues between an entire Omicron St and ACE2.…”

“…9−12 There are only two available articles related to dynamic analysis, that is MD simulation, for the Omicron St-ACE2 system, and they concentrated on either the change of overall stability through simulation in vacuum environment 15 or the influence of individual mutation on the interaction. 16 However, neither of them analyzed in detail the dynamics and the comprehensive interaction network including conserved residues between an entire Omicron St and ACE2.…”