Molecular recognition of SARS-CoV-2 spike protein with three essential partners: exploring possible immune escape mechanisms of viral mutants

Abstract

The COVID-19 epidemic is raging around the world, with the emergence of viral mutantstrains such as Delta and Omicron, posing severe challenges to people's health andquality of life. A full understanding life cycle of the virus in host cells helps to revealinactivation mechanism of antibody and provide inspiration for the development of anew-generation vaccines. In this work, molecular recognitions and conformational changes of SARS-CoV-2 spikeprotein mutants (i.e., Delta, Mu, and Omicron) and three essential partners (i.e.,membrane receptor hACE2, protease TMPRSS2, and antibody C121) both werecompared and analyzed using molecular simulations. Water basin and binding free energy calculations both show that the three mutantspossess higher affinity for hACE2 than WT, exhibiting stronger virus transmission. Thedescending order of cleavage ability by TMPRSS2 is Mu, Delta, Omicron, and WT,which is related to the new S1/S2 cutting site induced by transposition effect. Theinefficient utilization of TMPRSS2 by Omicron is consistent with its primary entry into cells via the endosomal pathway. In addition, RBD-directed antibody C121 showed obvious resistance to Omicron, which may have originated from high fluctuation ofapproaching angles, high flexibility of I472-F490 loop, and reduced binding ability. According to the overall characteristics of the three mutants, high infectivity, highimmune escape, and low virulence may be the future evolutionary selection of SARS-CoV-2. In a word, this work not only proposes the possible resistance mechanism ofSARS-CoV-2 mutants, but also provides theoretical guidance for the subsequent drugdesign against COVID-19 based on S protein structure.