Large-Scale Density Functional Theory Transition State Searching in Enzymes.
Linear-scaling quantum mechanical density functional theory calculations have been applied to study the rearrangement of chorismate to prephenate in large-scale models of the Bacillus subtilis chorismate mutase enzyme. By treating up to 2000 atoms at a consistent quantum mechanical level of theory, we obtain an unbiased, almost parameter-free description of the transition state geometry and energetics. The activation energy barrier is calculated to be lowered by 10.5 kcal mol(-1) in the enzyme, compared with the equivalent reaction in water, which is in good agreement with experiment. Natural bond orbital analysis identifies a number of active site residues that are important for transition state stabilization in chorismate mutase. This benchmark study demonstrates that linear-scaling density functional theory techniques are capable of simulating entire enzymes at the ab initio quantum mechanical level of accuracy.
†Theory of Condensed Matter Group, Cavendish Laboratory, 19 JJ Thomson Avenue, Cambridge CB3 0HE, United Kingdom.
Greg
G
Lever
†Theory of Condensed Matter Group, Cavendish Laboratory, 19 JJ Thomson Avenue, Cambridge CB3 0HE, United Kingdom.|‡Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States.
Daniel J
DJ
Cole
¶Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom.
Richard
R
Lonsdale
¶Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom.
Kara E
KE
Ranaghan
§University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
David J
DJ
Wales
¶Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom.
Adrian J
AJ
Mulholland
∥School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, United Kingdom.
Chris-Kriton
CK
Skylaris
†Theory of Condensed Matter Group, Cavendish Laboratory, 19 JJ Thomson Avenue, Cambridge CB3 0HE, United Kingdom.
Mike C
MC
Payne
density functional calculations; energy landscape; enzyme catalysis; linear scaling; transition state