3(a)

3(a). binding affinity by increasing the electrostatic interactions of the RBD-hACE2 complex. Moreover, fourteen neutralizing antibodies/nanobodies complexed with RBD were used to explore the effects of the mutations in Omicron RBD on their binding affinities. The calculation results indicate that OSI-027 the key mutations E484A and Y505H reduce the binding affinities to RBD OSI-027 for most of the studied neutralizing antibodies/nanobodies, mainly attributed to the elimination of the original favorable gas-phase electrostatic and hydrophobic interactions between them, respectively. Our results provide valuable information for developing effective vaccines and antibody/nanobody drugs. Keywords: SARS-CoV-2, Omicron variant, RBD, Key mutations, Molecular dynamics simulation, MMGBSA, Binding affinity, Immune escape Graphical abstract Open in a separate window 1.?Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continuously evolves to acquire mutations that may affect its transmissibility or immune-evasive ability [1,2]. So far, many variants have appeared, among which the recently emerged Omicron variant and its sub-lineages have led to new waves of infection worldwide [3]. The Omicron variant first arose as BA.1 sub-lineage, which carries 15 mutations in the receptor-binding domain (RBD) of the spike protein compared to the prototype virus [4,5]. The spike RBD directly interacts with the receptor human angiotensin-converting enzyme 2 (hACE2) on the host cells, and the far more mutations in Omicron RBD than earlier variants enable it to be more transmissible and immune-escapable [6]. Statistical analysis of genomic surveillance data showed that the transmissibility of Omicron was about 3.31-fold higher than that of Delta [7,8]. Computational and experimental studies suggested that the higher transmissibility of Omicron was potentially attributed to its increased binding affinity to the receptor hACE2 [9,10]. In addition, numerous experimental tests demonstrated that the Omicron variant substantially evades host immunity induced by vaccination or previous infection [11,12], and escapes the neutralization of existing therapeutic monoclonal antibodies [11,13]. Not all the mutations occurring in RBD contribute equally to the binding of Omicron with the receptor or the antibodies. Identifying key mutations responsible for the changes in RBD-receptor and RBD-antibody binding affinities is important for better understanding the mechanism behind Omicron’s increased transmissibility and immune escapability, which can provide valuable information for broad-spectrum vaccine design and therapeutic drug development. Some previous studies have employed computational method to investigate the binding strength of Omicron RBD to the receptor hACE2 as well as the specific therapeutic antibodies [[14], [15], [16], [17], [18], [19], [20], [21], [22], [23]]. However, it is still not completely understood which and how amino acid mutations essentially alter the Omicron RBD-hACE2 interactions. In addition, a comprehensive understanding of the mechanism behind the immune escape of Omicron from a panel of neutralizing antibodies is still lacking. In the present study, all atomic molecular dynamics (MD) simulation combined with molecular mechanics generalized Born surface area (MM/GBSA) was used to evaluate the impacts of the mutations on the binding of Omicron RBD with the receptor hACE2 and a panel of representative antibodies. Then, per-residue energy decomposition analysis was performed to identify the key mutations primarily contributing to the changes in the binding affinity of Omicron RBD with hACE2 and representative antibodies. 2.?Materials and methods 2.1. Preparation of the RBD-hACE2 and RBD-antibody complex structures The coordinate file for the prototype RBD complexed with the receptor hACE2 was obtained from the protein data bank (PDB) with the accession code 6M0J [24]. The complex structures formed by OSI-027 the prototype RBD and 14 neutralizing antibodies/nanobodies were also obtained from PDB with the accession codes shown in Table 1 . The UCSF chimera software was used to introduce the mutations appearing on the RBD of the Omicron variant, with the sidechain conformation of the mutations determined by the Dunbrack 2010 library. Table 1 The complex Rabbit polyclonal to AGBL2 formed by RBD and neutralizing nanobodies/antibodies studied in this work. is the molecular mechanics contribution in a vacuum, which contains internal, van der Waals, and electrostatic interactions;.