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.