Essential dynamics of lipase binding sites: the effect of inhibitors of different chain length |
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Authors: | Peters GH; van Aalten DM; Svendsen A; Bywater R |
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Affiliation: | Chemistry Department III, H.C. Orsted Institute, University of Copenhagen, Copenhagen O, Denmark. |
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Abstract: | The biochemical activity of enzymes, such as lipases, is often associated
with structural changes in the enzyme resulting in selective and
stereospecific reactions with the substrate. To investigate the effect of a
substrate and its chain length on the dynamics of the enzyme, we have
performed molecular dynamics simulations of the native Rhizomucor miehei
lipase (Rml) and lipase-dialkylphosophate complexes, where the length of
the alkyl chain ranges from two to 10 carbon atoms. Simulations were
performed in water and trajectories of 400 ps were used to analyse the
essential motions in these systems. Our results indicate that the internal
motions of the Rml and Rml complexes occur in a subspace of only a few
degrees of freedom. A high flexibility is observed in solvent-exposed
segments, which connect beta-sheets and helices. In particular, loop
regions Gly35-Lys50 and Thr57-Asn63 fluctuate extensively in the native
enzyme. Upon activation and binding of the inhibitor, involving the
displacement of the active site loop, these motions are considerably
suppressed. With increasing chain length of the inhibitor, the fluctuations
in the essential subspace increase, levelling off at a chain length of 10,
which corresponds to the size of the active-site groove.
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