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Sensitivity of molecular dynamics simulations to the choice of the X-ray structure used to model an enzymatic reaction

Department of Chemistry and Supercomputer Institute, University of Minnesota, Minneapolis, Minnesota 55455, USA

(RECEIVED December 13, 2003; FINAL REVISION January 19, 2004; ACCEPTED January 20, 2004)

A subject of great practical importance that has not received much attention is the question of the sensitivity of molecular dynamics simulations to the initial X-ray structure used to set up the calculation. We have found two cases in which seemingly similar structures lead to quite different results, and in this article we present a detailed analysis of these cases. The first case is acyl-CoA dehydrogenase, and the chief difference of the two structures is attributed to a slight shift in a backbone carbonyl that causes a key residue (the proton-abstracting base) to be in a bad conformation for reaction. The second case is xylose isomerase, and the chief difference of the two structures appears to be the ligand sphere of a Mg²⁺ metal cofactor that plays an active role in catalysis.

Keywords: combined quantum mechanics/molecular mechanics; molecular dynamics; potential of mean force; structure-based enzyme modeling

Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03504104.

Reprint requests to: Donald G. Truhlar, Department of Chemistry and Supercomputer Institute, University of Minnesota, Minneapolis, MN 55455, USA; e-mail: truhlar{at}umn.edu; fax: (612) 626-9390.

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