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).