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bioRxiv · 10.1101/088468

Simulations of CYP51A from Aspergillus fumigatus in a model bilayer provide insights into triazole drug resistance

Nash, A.·Rhodes, J.
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Abstract

1Azole 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.

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Nash, A., Rhodes, J.. 2016-11-17. Simulations of CYP51A from Aspergillus fumigatus in a model bilayer provide insights into triazole drug resistance. https://doi.org/10.1101/088468

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