TY - JOUR T1 - Simulations of <em>CYP51A</em> from <em>Aspergillus fumigatus</em> in a model bilayer provide insights into triazole drug resistance JF - bioRxiv DO - 10.1101/088468 SP - 088468 AU - Anthony Nash AU - Johanna Rhodes Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/11/17/088468.abstract N2 - Azole antifungal drugs target CYP51A in Aspergillus fumigatus by binding with the active site of the protein, blocking ergosterol biosynthesis. Resistance to azole anti-fungal drugs is now common, with a leucine to histidine amino acid substitution at position 98 the most frequent, conferring resistance to itraconazole. In this study, we create a homology model of CYP51A using a recently published crystal structure of the paralog protein CYP51B. The derived structures, wild-type and L98H mutant, are positioned within a lipid membrane bilayer and subjected to molecular dynamics simulations in order improve the accuracy of both models. The structural analysis from our simulations suggests a decrease in active site surface from the formation of hydrogen bonds between the histidine substitution and neighbouring polar side chains, potentially preventing the binding of azole drugs. This study yields a biologically relevant structure and set dynamics of the A. fumigatus Lanosterol 14 alpha-demethylase enzyme and provides further insight into azole antifungal drug resistance. ER -