jp5b11966_si_001.pdf (857.83 kB)
Enhancing Paradynamics for QM/MM Sampling of Enzymatic Reactions
journal contribution
posted on 2016-02-11, 00:00 authored by Jerônimo Lameira, Ilya Kupchencko, Arieh WarshelDespite the enormous increase in
computer power, it is still extremely
challenging to obtain computationally converging sampling of ab initio
QM/MM (QM(ai)/MM) free energy surfaces in condensed
phases. The sampling problem can be significantly reduced by the use
of the reference potential paradynamics (PD) approach, but even this
approach still requires major computer time in studies of enzymatic
reactions. To further reduce the sampling problem we developed here
a new PD version where we use an empirical valence bond reference
potential that has a minimum rather than a maximum at the transition
state region of the target potential (this is accomplished conveniently
by shifting the EVB of the product state). Hence, we can map the TS
region in a more efficient way. Here, we introduce and validate the
inverted EVB PD approach. The validation involves the study of the
SN2 step of the reaction catalyzed by haloakene dehalogenase
(DhlA) and the GTP hydrolysis in the RasGAP system. In addition, we
have also studied the corresponding reaction in water for each of
the systems described here and the reaction involving trimethylsulfonium
and dimethylamine in solution. The results are encouraging and the
new strategy appears to provide a powerful way of evaluating QM(ai)/MM activation free energies.