Cytochrome P450 (CYPs) are crucial heme-containing enzymes that metabolize drugs and endogenous compounds. In humans, 57 CYP isoforms have been identified, with over 200 mutations linked to severe disorders. Our comprehensive computational study assessed the reason for the pathogenicity of mutations by comparing pathogenic and non-pathogenic variants. We analyzed 25,94,151 mutations across 26 CYP structures using structure- and sequence-based methods, revealing a meaningful stability pattern: non-pathogenic > all > pathogenic mutation datasets. Notably, pathogenic mutations were predominantly buried within CYP structures, indicating a higher potential for pathogenesis. We identified three key amino acid properties affected by mutations: Gibbs free energy, isoelectric point, and volume. Furthermore, diseased mutations significantly reduced positive residue content, particularly due to arginine mutations, which directly influenced the isoelectric point. Our findings indicate a greater likelihood of pathogenic mutations occurring at conserved sites, disrupting CYP function. A higher frequency of pathogenic mutations was observed in heme sites, primarily involving arginine, which may interfere with arginine-heme interactions. Molecular docking revealed a differential binding of heme in wild-type and pathogenic CYPs. This study provides a foundational analysis of mutation effects across multiple CYPs. It models the chemical basis of CYP-related pathogenicity, facilitating the development of a semi-quantitative disease prediction model.
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