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.