Molecular and structural insights into SARS-CoV-2 evolution: from BA.2 to XBB subvariants

Abstract

Due to the incessant emergence of various SARS-CoV-2 variants with enhanced fitness in the human population, controlling the COVID-19 pandemic has been challenging. Understanding how the virus enhances its fitness during a pandemic could offer valuable insights for more effective control of viral epidemics. In this manuscript, we review the evolution of SARS-CoV-2 from early 2022 to the end of 2023-from Omicron BA.2 to XBB descendants. Focusing on viral evolution during this period, we provide concrete examples that SARS-CoV-2 has increased its fitness by enhancing several functions of the spike (S) protein, including its binding affinity to the ACE2 receptor and its ability to evade humoral immunity. Furthermore, we explore how specific mutations modify these functions of the S protein through structural alterations. This review provides evolutionary, molecular, and structural insights into how SARS-CoV-2 has increased its fitness and repeatedly caused epidemic surges during the pandemic.

Keywords: Omicron; SARS-CoV-2; evolution; molecular phylogenetic; spike; structural biology.

Fig 1

Epidemiology and evolution of BA.2-related lineages. (A) Repeated transitions of epidemic SARS-CoV-2 lineages from 1 November 2021 to 29 February 2024. The source data were obtained from GISAID (https://gisaid.org/; EPI SET ID: EPI_SET_240423yq). (B) Schematic lineage tree of major epidemic lineages provided by Nextclade. This figure was sourced from Nextclade (https://clades.nextstrain.org/) and used under the CC-BY 4.0 license. (C) Comparison of mutations in the S protein among major lineages. When different types of substitutions occur at the same amino acid position, these substitutions are displayed together, indicating the types of substitutions. The source data were obtained from GISAID (EPI SET ID: EPI_SET_240423yq).

Fig 2

Structural and virological summaries of the evolution of BA.2-related lineages. (A) A schematic of descendants after BA.2 was sorted over time (refer to Fig. 1A). The ACE2-binding affinity and neutralizing antibody evasion ability compared to those of the ancestral lineage on the left are shown under each variant name. In each variant, the cryo-EM structure or schematic of the S protein trimer alone is shown in the bottom left, and the zoom-up view of the mutation of interest for each variant is shown in the bottom right. PDB IDs: BA.5, 7XWA; BA.2.75, 8ASY; BQ.1.1, 8IF2; XBB.1, 8IOV; XBB.1.5, 8JYP; EG.5.1, 8XLN. EMDB IDs: BA.5, 33325; BA.2.75, 34221; XBB.1, 35622; XBB.1.5, 36724; EG.5.1, 37651. (B) A schematic diagram of the sequence gap bordered before/after BA.1 and the structural gap bordered before/after BA.2. In sequences, the difference between pre-Omicron and Omicron is obvious, but in the RBD up/down states of the S proteins, they are separated at the boundary of BA.1 and BA.2. In the structures of S-protein trimer, the RBDs are highlighted in red (the other areas are gray).