{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T08:14:31Z","timestamp":1788509671132,"version":"build-2803163510"},"reference-count":35,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["FEBS Open Bio"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:p>\n                    Fc\u03b3RI is a high\u2010affinity receptor for IgG, associated with autoimmune disease pathology and determines clinical responses to antibody\u2010based immunotherapies. Fc\u03b3RI 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,\n                    <jats:italic>FCGR1A,<\/jats:italic>\n                    using codon\u2010based selection tests on aligned 1\u20131 orthologous sequences from placental mammals (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200932). Signatures of positive selection have occurred at several locations within the gene, with two sites (H\n                    <jats:sup>148<\/jats:sup>\n                    (M2a \u03c9 0.997 &amp; M8 \u03c9\u2009=\u20090.993)) and (W\n                    <jats:sup>149<\/jats:sup>\n                    (M2a \u03c9\u2009=\u20090.999 &amp; M8 \u03c9\u2009=\u20091.000)) exhibiting highest posterior probabilities, suggesting strong evidence of positive selection; these positions are known to form one of the Fc\u03b3RI\u2010IgG binding interfaces. We employed ancestral reconstruction to statistically infer prior codon sequences at these sites and identified ancestral H\n                    <jats:sup>148<\/jats:sup>\n                    P and W\n                    <jats:sup>149<\/jats:sup>\n                    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 Fc\u03b3RI\u2010IgG of modern\u2010day\n                    <jats:italic>Homo sapiens<\/jats:italic>\n                    . 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\n                    <jats:sup>148<\/jats:sup>\n                    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\n                    <jats:sup>149<\/jats:sup>\n                    R substitutions demonstrate an implication for electron conjugation. Examining key sites at this binding Fc\u03b3RI\u2010IgG 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.\n                  <\/jats:p>","DOI":"10.1002\/2211-5463.70247","type":"journal-article","created":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T05:50:23Z","timestamp":1777701023000},"page":"1708-1725","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular dynamics simulations of positively selected codons in\n                    <scp>Fc\u03b3RI<\/scp>\n                    reveal novel biochemical binding properties"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3700-7006","authenticated-orcid":false,"given":"David A.","family":"Young","sequence":"first","affiliation":[{"name":"Molecular 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Activity and Life Sciences University of Northampton  UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3686-2799","authenticated-orcid":false,"given":"Amit","family":"Nathubhai","sequence":"additional","affiliation":[{"name":"Molecular Bioscience Research Group, Centre for Physical Activity and Life Sciences University of Northampton  UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauricio","family":"Cafiero","sequence":"additional","affiliation":[{"name":"School of Chemistry, Food and Pharmacy University of Reading  Reading UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7974-2178","authenticated-orcid":false,"given":"Lee Richard","family":"Machado","sequence":"additional","affiliation":[{"name":"Molecular Bioscience Research Group, Centre for Physical Activity and Life Sciences University of Northampton  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