Three hydrolases and a transferase: comparative analysis of active-site dynamics via the BioSimGrid database

Abstract

Comparative molecular dynamics (MD) simulations enable us to explore the conformational
dynamics of the active sites of distantly related enzymes. We have used the BioSimGrid
(http://www.biosimgrid.org) database to facilitate such a comparison. Simulations of four enzymes
were analyzed. These included three hydrolases and a transferase, namely acetylcholinesterase,
outer-membrane phospholipase A, outer-membrane protease T, and PagP (an outer membrane
enzyme which transfers a palmitate chain from a phospholipid to lipid A). A set of 17 simulations
were analyzed corresponding to a total of ~0.1 μs simulation time. A simple metric for active site
integrity was used to demonstrate the existence of clusters of dynamic conformational behaviour of
the active sites. Small (i.e. within a cluster) fluctuations appear to be related to the function of an
enzymatically active site. Larger fluctuations (i.e. between clusters) correlate with transitions
between catalytically active and inactive states. Overall, these results demonstrate the potential of a
comparative MD approach to analysis of enzyme function. This approach could be extended to a
wider range of enzymes using current high throughput MD simulation and database methods.

Keywords:
biomolecular simulation, database, data mining, molecular dynamics, catalytic triad,
conformational change

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