Spike conformation transition in SARS-CoV-2 infection

TL;DR

This paper presents a theoretical model for the conformational transition of the SARS-CoV-2 spike protein, linking amino acid mutations to changes in infectivity and predicting potential new variants based on energy considerations.

Contribution

It introduces a first-principles theory connecting spike protein conformation, mutations, and infectivity, including quantitative estimates of elastic energy changes.

Findings

Mutations can bias the spike towards the open conformation, enhancing infectivity.

The theory explains the impact of specific mutations like D614G and 501Y.

Predicted new variants based on amino acid changes in RBD interface.

Abstract

A theory on the conformation transition for SARS-CoV-2 spike protein (S) is proposed. The conformation equilibrium between open (up) and closed (down) conformations of receptor binding domain (RBD) of the spike is studied from the first-principle. The conformational state population is deduced from the free energy change in conformation transition of S protein. We demonstrated that the free energy includes two parts, one from the multi-minima of conformational potential and another from the variation of structural elasticity. Both factors are dependent of amino acid mutation. The former is related to the change of affinity of RBD to ACE 2 due to the mutation in the subdomain RBM (receptor binding motif) of RBD. The latter is caused by the change of elastic energy of S protein. When the affinity has increased significantly and/or the elastic energy has been reduced substantially the equilibrium is biased to the open conformation. Only then can the virus infection process continue. Possible new SARS-CoV-2 variants from amino acid mutations in 5-9 sites on RBD interface are predicted. The elastic energy variation needed for conformation transition is estimated quantitatively. Taking the elastic-structural change into account more virus variants are possible. Both the D614G mutation, the K986P mutation and the new variants 501Y in current SARS-CoV-2 pandemic can be interpreted from the presented theory. The comparison of the infectivity of SARS-CoV-2 with SARS-CoV-1 is made from the point of conformation equilibrium. Why the virus entrance takes priority in lower temperature and higher humidity is interpreted by the present theory. The conformational transition influenced by electromagnetic field is also discussed briefly.