Molecular Dynamics Simulations on Aspergillus niger Monoamine Oxidase: Conformational Dynamics and Inter‐monomer Communication Essential for Its Efficient Catalysis

Abstract

AbstractAspergillus niger Monoamine Oxidase (MAO‐N) is a homodimeric enzyme responsible for the oxidation of amines into the corresponding imine. Laboratory evolved variants of MAO‐N in combination with a non‐selective chemical reductant represents a powerful strategy for the deracemisation of chiral amine mixtures and, thus, is of interest for obtaining chiral amine building blocks. As we reported recently, MAO‐N presents a rich conformational dynamics with a flexible β‐hairpin region that can adopt closed, partially closed and open states. Despite the β‐hairpin conformational dynamics is altered along the laboratory evolutionary pathway of MAO‐N, the connection between the β‐hairpin conformational dynamics and how this affects active site catalysis still remains unclear. In this work, we use accelerated molecular dynamics to elucidate the potential interplay between the β‐hairpin conformational dynamics and catalytic activity in MAO‐N wild type (WT) and its evolved D5 variant. Our study reveals a delicate communication between both MAO‐N monomers that impacts the active site architecture, and thus its catalytic efficiency. In both MAO‐N WT and the laboratory evolved D5 variant, the β‐hairpin conformation in one of the monomers affects the productive binding of the substrate in the active site of the other subunit. However, both MAO‐N WT and D5 variants show a quite different behaviour due to the impact of distal mutations introduced experimentally with Directed Evolution on the conformational dynamics of the enzyme.magnified image