Abstract

Human cytochrome P450 1A2 (CYP1A2) plays a critical role in the mechanism of drug metabolism the understanding of which constitutes a cornerstone in drug design processes. Its relevance has furthered in view of recent trends in tailor made medicine, since the enzyme's activity differs according to the mutations orsingle nucleotide polymorphisms (SNP's) in the respective genetic coding region. Here we investigate the structural variation induced by selected single mutations that have been reported on the CYP1A2 enzyme. Weapplied our graph theory approach and mainly focus on the differences in 3D structure between the "wild-type" and the mutant structures in terms of the structural flexibility changes that may arise as consequence of the mutations. Based on this information we have additionally inferred internal collective motions that may affect the function of the enzyme using molecular dynamics simulations. Our results show that most of the studied mutations are located in loops and regions of high flexibility and the simulation of their dynamic behavior sheds light on probable consequences of these mutations on the function of the enzyme.

Key words: Cytochrome P450 1A2 (CYP1A2), single nucleotide polymorphism (SNP), molecular flexibility, molecular dynamics simulation, graph theory.