In silico evaluation of the interaction between ACE2 and SARS-CoV-2 Spike protein in a hyperglycemic environment.
Level 5 - mechanism / opinion, no new human data
In silico computational molecular modeling study without human or biological validation data.
PubMed 34819560 · doi:10.1038/s41598-021-02297-w
What was done
Researchers conducted an in silico computational modeling analysis using the X-ray crystallographic structure of the SARS-CoV-2 Spike Receptor-Binding Domain (RBD) and human ACE2 complex. They simulated the effect of non-enzymatic glycation of surface lysine residues across four states: (1) both native, (2) native ACE2 with glycated Spike, (3) glycated ACE2 with native Spike, and (4) both ACE2 and Spike glycated. They evaluated the number of polar bonds (hydrogen bonds and salt bridges) and non-polar contacts (van der Waals and aromatic interactions) across these configurations.
What was found
Compared to the native state, which formed 10 polar bonds, the number of polar bonds decreased to 6 for native ACE2/glycated Spike, 6 for glycated ACE2/native Spike, and 4 when both ACE2 and Spike were glycated. Non-polar contacts (van der Waals and aromatic interactions) also decreased significantly following glycation of lysine residues, indicating reduced binding affinity between ACE2 and Spike in simulated hyperglycemic states.
Why it matters
While hyperglycemia is clinically associated with worse COVID-19 outcomes, these computational findings suggest that direct ACE2-Spike affinity may actually decrease with non-enzymatic glycation, leading authors to hypothesize that alternative entry pathways might be involved.
Limits
This is purely an in silico structural simulation without experimental in vitro, in vivo, or clinical validation. Biological factors such as dynamic protein conformation, cellular membrane dynamics, additional glycation targets, and alternative receptors were not empirically tested.
Cited by
- contradicts High blood glucose crystallizes around ACE2 molecules to keep them open, increasing susceptibility to COVID-19 infection.