Results
SARS-CoV-2 viral spike amino acid sequences from strains infecting patients in Europe exhibited a predominance of glycine at amino acid position 614 in the viral spike (G614), while countries in the Far East exhibited a high percentage of D614 viral spikes. Based on case fatality rate (CFR) and SARS-CoV-2 viral spike sequence data available on April 6, 2020, both the average and median CFR correlate strongly (p< 0.02) with the proportion of viruses in the same geographic region bearing aspartate at position 614 (D614) in the viral spike (Figure 1 ). For example, the proportion of recorded viruses in China exhibiting D614 was nearly 100% and this country exhibited the second lowest average or median CFR.
As of the time of writing, the complete daily data necessary to calculate the CFR for US states was not available, so this correlation could not be plotted for US states, however, the percentage of viruses in each state exhibiting aspartate (D) instead of glycine (G) at amino acid residue number 614 in the viral spike (S) protein can be assessed (Table 1 ), revealing dramatically lower G614 in Western USA states.
Modeling of the molecular impact of aspartate (D) or glycine (G) at position 614 in the 3D structure of the viral envelope spike trimer revealed that G is a less stable occupant from a biophysical point of view specifically in the “up” state of the viral spike, in which the surface of the viral spike that binds human ACE-2 is exposed and accessible to this host cell surface protein. The “down” or unliganded form shows no or mildly the opposite effect. The model predicts the G mutation to be destabilizing relative to D for the local area around the amino acid 614 position, apparently from loss of packing with the side-chain of threonine 858 from the helical core stalk of the viral spike of an adjacent monomer (Figure 2 ), creating an unstable cavity in the protein. Cavities in the protein core or at protein interfaces are well known to destabilize protein tertiary and quaternary structure5. Thus, the structures predict a higher energy barrier for rearrangement of the viral spikes harboring G614 to their infectious form (i.e. the conformation of the viral spike that is most optimal for binding host ACE-2, which is the first animal/human receptor to which the virus binds in order to infect and cause disease).