Characterising the combined eects of cytochrome P450 missense variants within the star allele nomenclature
Date
2024
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
University of the Witwatersrand, Johannesburg
Abstract
Genetic variations in Cytochrome P450 (CYP) enzymes shape drug responses. However, many CYP haplotypes (star alleles) lack functional annotations, posing a barrier to under- standing drug metabolism comprehensively. To address this, our study investigates combined missense variant eects on CYP enzyme structures, analyzing 261 variants across 91 CYP haplotypes. We utilized Normal Mode Analysis (NMA; FoldX and ENCoM) to explore variant impact on protein stability. Subsequently, we conducted Molecular Dynamics (MD) simulations on key alleles, CYP2D6*2 and CYP2D6*17, to reveal star allele impact on protein dynamics. Integrating NMA and MD, we uncover the interactions that collectively shape the conformation and attributes of CYP enzymes. Notably, our investigation highlights significant deviations between wild-type and CYP2D6*17 -encoded proteins in the F/G loop region, pivotal for CYP functionality. Additionally, we compare
NMA results with CYP2C9 and CYP2C19 Deep Mutational Scanning (DMS) results, identifying 65% concordance. Furthermore, our NMA predictions show 80% concordance with commonly used Variant Eect Predictor tools. This alignment underscores our approach’s reliability in predicting variant eects. Our study illuminates missense variants’ nuanced impact on CYP protein structures, significant for personalized medicine and drug response prediction, as accurate drug response predictions hinge on a comprehensive understanding of CYP missense variants. Moreover, our study highlights multi-scalemodelling potential for interpreting CYP missense variants, especially in star alleles. The synergy of NMA, MD simulation, and assays like DMS is invaluable, each with distinct
strengths and limitations. This research deepens our understanding of the complexity of CYP metabolism profiles, providing insights into the functional assessment of CYP star alleles and missense variants with unknown functional classifications.
Description
A dissertation submitted in fulfillment of the requirements for the degree of Master of Science in Medicine to the Faculty of Health Sciences, School of Pathology University of the Witwatersrand, Johannesburg 2024
Keywords
CYP, Missense variants, Multiscale modeling, Pharmacogenomics, PharmVar, UCTD
Citation
Khoza, Nhlamulo. (2024). Characterising the combined eects of cytochrome P450 missense variants within the star allele nomenclature [Master’s dissertation, University of the Witwatersrand, Johannesburg]. WireDSpace.