Transition path sampling presents an advantage for the study of dynamic complex systems in that no prior restraints on potential paths through phase space are required. As such, the ensemble of trajectories generated from a calculation using this method should be free of any preconception of mechanism. This presents a unique opportunity to study both reaction mechanism and free energy profiles of complex reactions. Free energy calculations using TPS has previously been limited to full rate calculations from which free energy can be inferred. We present a method that utilizes the apparent force on a constituent particles to calculate the reversible work that is done on this particle in each reactive trajectory. The average of this work is the free energy experienced by the particle in the ensemble calculation. For example, if one is studying a hydrogen transfer reaction, then the free energy barrier seen by the hydrogen is the average of reversible work felt by the hydrogens in the ensemble of reactive trajectories. (Note - this is not necessarily the experimentally measured free energy of the entire enzyatic process.) We will present a number of cases of both free energy and reaction coordinate calculations that demonstrate that such calculations can both reproduce trends in experiments, and also provide interesting new insights into mechanism. Like all free energy methods, which inherently involve configurational averaging, this method suffers from potential incomplete averaging, but the result are not subject to the usual sampling biases introduced by such methods as umbrella sampling.

Free energy calculations and reaction coordinates from transition path sampling of enzymatic reactions

251st National Meeting (2016)

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