Compensatory epistasis explored by molecular dynamics simulations

A non-negligible proportion of human pathogenic variants are known to be present as wild type in at least some non-human mammalian species. The standard explanation for this finding is that molecular mechanisms compensatory epistasis can alleviate the mutations’ otherwise effects. Examples compensated have been described literature but interacting residue(s) postulated play a role rarely ascertained. In study, examination five X-chromosomally encoded proteins (FIX, GLA, HPRT1, NDP and OTC) allowed us identify several candidate variants. Strong evidence compensated/compensatory pair amino acids coagulation FIXa protein (involving residues 270 271) was found variety Both acid located within 60-loop, spatially close 39-loop performs key serine proteases. To understand nature underlying interactions, dynamics simulations were performed. predicted conformational change consequent Glu270Lys substitution (associated with hemophilia B) appears impair protein’s interaction its substrate but, importantly, such steric hindrance largely mitigated those carry residue (Pro271) neighboring position.