Single Nucleotide Polymorphism Induces Divergent Dynamic Patterns in CYP3A5: A Microsecond Scale Biomolecular Simulation of Variants Identified in Sub-Saharan African Populations.

Houcemeddine Othman,Scott Hazelhurst,Jorge E B Da Rocha

doi:10.3390/ijms22157786

Abstract

Pharmacogenomics aims to reveal variants associated with drug response phenotypes. Genes whose roles involve the absorption, distribution, metabolism, and excretion of drugs, are highly polymorphic between populations. High coverage whole genome sequencing showed that a large proportion of the variants for these genes are rare in African populations. This study investigated the impact of such variants on protein structure to assess their functional importance. We used genetic data of CYP3A5 from 458 individuals from sub-Saharan Africa to conduct a structural bioinformatics analysis. Five missense variants were modeled and microsecond scale molecular dynamics simulations were conducted for each, as well as for the CYP3A5 wildtype and the Y53C variant, which has a known deleterious impact on enzyme activity. The binding of ritonavir and artemether to CYP3A5 variant structures was also evaluated. Our results showed different conformational characteristics between all the variants. No significant structural changes were noticed. However, the genetic variability seemed to act on the plasticity of the protein. The impact on drug binding might be drug dependant. We concluded that rare variants hold relevance in determining the pharmacogenomics properties of populations. This could have a significant impact on precision medicine applications in sub-Saharan Africa.

Highlights

The fate of drug molecules is determined by a set of biological processes controlling the Absorption, Distribution, Metabolism, and Excretion (ADME) in the organism
To evaluate the extent of rare variants genetic diversity affecting the gene product functionality, we extended our analysis by focusing on CYP3A5 gene based on the data from high coverage whole genome sequencing from individuals from sub-Saharan Africa, combined with 1000 Genome Project data
Five missense variants were identified in the source African populations of this study; all are rare with frequencies below 0.006 (Table 1)

Summary

Introduction

The fate of drug molecules is determined by a set of biological processes controlling the Absorption, Distribution, Metabolism, and Excretion (ADME) in the organism. The balance between the induction of the therapeutic effect and undesirable outcomes depends on the set of proteins encoding the ADME functions. Among these proteins, the CYP P450 superfamily is an important group of enzymes which play vital roles in Phase I metabolism of multiple drug types. Other variants of clinical importance include CYP3A5*6 and CYP3A5*7 which cause a protein truncation and a reading frame shift respectively [3]. The frequencies of these three major alleles are population dependant, on ethnicity or ancestry. Variant levels of significance response have been noted between different populations as well as within populations of the same ethnic composition

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Conclusion