Issue 15, 2017, Issue in Progress

Complete sampling of an enzyme reaction pathway: a lesson from gas phase simulations


This work addresses the sampling issue commonly accompanying the simulation of chemical reactions. Very often the sampling is severely limited by complexity of the phase space, possibly leading to poorly converged or inaccurate free energy profiles. We explored the factors governing the completeness of reaction path sampling for the rate limiting step of phenylethylamine oxidation by lumiflavin in the gas phase, a reaction important for the pharmacology of the central nervous system. The simulations utilize the free energy perturbation sampling technique together with the empirical valence bond methodology for the free energy calculations. The simplicity of the system allows for the acquisition of fully converged free energy profiles, even for simulation free of restraints. The bottleneck for convergence is in the noticeably poorer sampling statistics in the transition state region, which is resolved by performing sufficiently long simulation to ensure reversibility of all processes accompanying the reaction. In the present case, convergence is attained in microseconds of simulation, but the required simulation time generally depends on the complexity of the potential energy surface pertinent to the reaction. Accordingly, the use of restraints reduces the complexity of the phase space, decreasing the required time by about an order of magnitude. In the case of elementary nucleophilic substitution with even simpler potential energy surface convergence is reached already at a timescale of few nanoseconds. For related biomolecular reactions embedded in an enzyme, significantly longer simulation times may be needed, rendering the sampling problem exceedingly difficult and representing a challenge for advanced sampling techniques. Accordingly, suggestions are given for optimal simulation of biomolecular reactions based on the presently employed techniques and under the aforementioned limitations.

Graphical abstract: Complete sampling of an enzyme reaction pathway: a lesson from gas phase simulations

Article information

Article type
07 Dec 2016
16 Jan 2017
First published
27 Jan 2017
This article is Open Access
Creative Commons BY license

RSC Adv., 2017,7, 8740-8754

Complete sampling of an enzyme reaction pathway: a lesson from gas phase simulations

J. Stare, RSC Adv., 2017, 7, 8740 DOI: 10.1039/C6RA27894A

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