Evolution of Sequence and Structure of SARS-CoV-2 Spike Protein: A Dynamic Perspective

[Image: see text] Novel coronavirus (SARS-CoV-2) enters its host cell through a surface spike protein. The viral spike protein has undergone several modifications/mutations at the genomic level, through which it modulated its structure–function and passed through several variants of concern. Recent advances in high-resolution structure determination and multiscale imaging techniques, cost-effective next-generation sequencing, and development of new computational methods (including information theory, statistical methods, machine learning, and many other artificial intelligence-based techniques) have hugely contributed to the characterization of sequence, structure, function of spike proteins, and its different variants to understand viral pathogenesis, evolutions, and transmission. Laying on the foundation of the sequence–structure–function paradigm, this review summarizes not only the important findings on structure/function but also the structural dynamics of different spike components, highlighting the effects of mutations on them. As dynamic fluctuations of three-dimensional spike structure often provide important clues for functional modulation, quantifying time-dependent fluctuations of mutational events over spike structure and its genetic/amino acidic sequence helps identify alarming functional transitions having implications for enhanced fusogenicity and pathogenicity of the virus. Although these dynamic events are more difficult to capture than quantifying a static, average property, this review encompasses those challenging aspects of characterizing the evolutionary dynamics of spike sequence and structure and their implications for functions.