title: 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 approximately 0.1 micros 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.
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.
authors.forename: Kaihsu
authors.initials: K
authors.lastname: Tai
authors.forename: Marc
authors.initials: M
authors.lastname: Baaden
authors.forename: Stuart
authors.initials: S
authors.lastname: Murdock
authors.forename: Bing
authors.initials: B
authors.lastname: Wu
authors.forename: Muan Hong
authors.initials: MH
authors.lastname: Ng
authors.forename: Steven
authors.initials: S
authors.lastname: Johnston
authors.forename: Richard
authors.initials: R
authors.lastname: Boardman
authors.forename: Hans
authors.initials: H
authors.lastname: Fangohr
authors.forename: Katherine
authors.initials: K
authors.lastname: Cox
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Essex
authors.forename: Mark S P
authors.initials: MS
authors.lastname: Sansom
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry; D001665:Binding Sites; D003198:Computer Simulation; D030562:Databases, Protein; D006867:Hydrolases / Q000737:chemistry*; D066298:In Vitro Techniques; D008958:Models, Molecular; D015394:Molecular Structure; D013816:Thermodynamics; D014166:Transferases / Q000737:chemistry*
chemical_list: D014166:Transferases; D006867:Hydrolases; D000110:Acetylcholinesterase