title: Membrane attachment facilitates ligand access to the active site in monoamine oxidase A.
abstract: Monoamine oxidase membrane enzymes are responsible for the catalytic breakdown of extra- and intracellular neurotransmitters and are targets for the development of central nervous system drugs. We analyzed the dynamics of rat MAOA by performing multiple independent molecular dynamics simulations of membrane-bound and membrane-free forms to clarify the relationship between the mechanics of the enzyme and its function, with particular emphasis on the significance of membrane attachment. Principal component analysis of the simulation trajectories as well as correlations in the fluctuations of the residues pointed to the existence of three domains that define the global dynamics of the protein. Interdomain anticorrelated movements in the membrane-bound system facilitated the relaxation of interactions between residues surrounding the substrate cavity and induced conformational changes which expanded the active site cavity and opened putative pathways for substrate uptake and product release. Such events were less pronounced in the membrane-free system due to differences in the nature of the dominant modes of motion. The presence of the lipid environment is suggested to assist in decoupling the interdomain motions, consistent with the observed reduction in enzyme activity under membrane-free conditions. Our results are also in accordance with mutational analysis which shows that modifications of interdomain hinge residues decrease the activity of rat MAOA in solution.
authors.affiliation: Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Rossen
authors.initials: R
authors.lastname: Apostolov
authors.forename: Yasushige
authors.initials: Y
authors.lastname: Yonezawa
authors.forename: Daron M
authors.initials: DM
authors.lastname: Standley
authors.forename: Gota
authors.initials: G
authors.lastname: Kikugawa
authors.forename: Yu
authors.initials: Y
authors.lastname: Takano
authors.forename: Haruki
authors.initials: H
authors.lastname: Nakamura
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain / Q000235:genetics; D002462:Cell Membrane / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004795:Enzyme Stability / Q000235:genetics; D005110:Extracellular Space / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008969:Molecular Sequence Data; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D013816:Thermodynamics
chemical_list: D007527:Isoenzymes; D008024:Ligands; D008995:Monoamine Oxidase