Characterizing the combined effects of cytochrome P450 missense variation within star allele definitions

Background: Cytochrome P450 (CYP) genetic variation largely impacts drug response. However, many CYP star alleles (haplotypes) lack functional annotation, impeding our understanding of drug metabolism mechanisms. We aimed to investigate the impact of missense variant combinations on CYP protein structures. Methods: Normal mode analysis was conducted on 261 missense variants within 91 CYP haplotypes. CYP2D6*2 and CYP2D6*17 were prioritized for molecular dynamics simulation. Results: Normal mode analysis and molecular dynamics highlight the effects of known CYP missense variants on protein stability and conformational dynamics. Missense variants within haplotypes may have intermodulating effects on protein structure and function. Conclusion: This study highlights the utility of multiscale modeling in interpreting CYP missense variants and particularly their combinations within various star alleles.