Abstract
FcγRI is a high‐affinity receptor for IgG, associated with autoimmune disease pathology and determines clinical responses to antibody‐based immunotherapies. FcγRI has a complex evolutionary history that is not fully understood, and to address this we explored signatures of positive selection in the receptor's functional gene,
FCGR1A,
using codon‐based selection tests on aligned 1–1 orthologous sequences from placental mammals (
n
= 32). Signatures of positive selection have occurred at several locations within the gene, with two sites (H
148
(M2a ω 0.997 & M8 ω = 0.993)) and (W
149
(M2a ω = 0.999 & M8 ω = 1.000)) exhibiting highest posterior probabilities, suggesting strong evidence of positive selection; these positions are known to form one of the FcγRI‐IgG binding interfaces. We employed ancestral reconstruction to statistically infer prior codon sequences at these sites and identified ancestral H
148
P and W
149
R codons at different nodes in the phylogeny. Employing molecular dynamics simulations, we determined how evolutionary changes at these sites may have influenced the binding of FcγRI‐IgG of modern‐day
Homo sapiens
. Measuring RMSD, free energy, radius of gyration, hydrogen bond formation, and analyzing free energy landscapes, we demonstrate that structural instability between mutant structures vs the WT counterpart; however, overall binding potential increases at position 148, yet decreases at 149 in potential. H
148
P protonation at physiological pH remains similar, yet during acidotic calculations, protonation is likely reduced, with predicted reduction in affinity for IgG. While ancestral W
149
R substitutions demonstrate an implication for electron conjugation. Examining key sites at this binding FcγRI‐IgG interface, our data demonstrate that these two codons have evolved in humans to be relatively insensitive to shifts in pH promoting a more stable interaction with the Fc portion of IgG during diseases that promote acidosis.