Unveiling diffusion pattern and structural impact of the most invasive SARS-CoV-2 spike mutation

Trucchi, Emiliano; Gratton, Paolo; Mafessoni, Fabrizio; Motta, Stefano; Cicconardi, Francesco; Bertorelle, Giorgio; D’Annessa, Ilda; Di Marino, Daniele

Starting in Wuhan, China, SARS-CoV-2 epidemics quickly propagated worldwide in less than three months, geographically sorting genomic variants in newly established propagules of infections. Stochasticity in transmission within and between countries and/or actual advantage in virus transmissibility could explain the high frequency reached by some genomic variants during the course of the outbreak. Using a suite of statistical, population genetics, and theoretical approaches, we show that the globally most represented spike protein variant (i.e., the G clade, A → G nucleotide change at genomic position 23,403; D → G amino acid change at spike protein position 614) i) underwent a significant demographic expansion in most countries not explained by stochastic effects or enhanced pathogenicity; ii) affects the spike S1/S2 furin-like site increasing its conformational plasticity (short range effect), and iii) modifies the internal motion of the receptor-binding domain affecting its cross-connection with other functional domains (long-range effect). Our study unambiguously links the spread of the G614 with a non-random process, and we hypothesize that this process is related to the selective advantage produced by a specific structural modification of the spike protein. We conclude that the different conformation of the S1/S2 proteolytic site is at the basis of the higher transmission rate of this invasive SARS-CoV-2 variant, and provide structural information to guide the design of selective and efficient drugs.