  Efficient computational methods that are capable of supporting experimental
measures obtained at constant values of pH and redox potential are important
tools as they serve to, among other things, provide additional atomic level
information that cannot be obtained experimentally. Replica Exchange is an
enhanced sampling technique that allows converged results to be obtained faster
in comparison to regular molecular dynamics simulations. In this work we report
the implementation, also available with GPU-accelerated code, of pH and redox
potential (E) as options for multidimensional REMD simulations in AMBER.
Previous publications have only reported multidimensional REMD simulations with
the temperature and Hamiltonian dimensions. In this work results are shown for
N-acetylmicroperoxidase-8 (NAcMP8) axially connected to a histidine peptide.
This is a small system that contains only a single heme group. We compare
results from E,pH-REMD, E,T-REMD and E,T,pH-REMD to one dimensional REMD
simulations and to simulations without REMD. We show that 2D-REMD simulations
improve sampling convergence in comparison to 1D-REMD simulations, and that
3D-REMD further improves convergence in comparison to 2D-REMD simulations.
Also, our computational benchmarks show that our multidimensional REMD
calculations have a small and bearable computational performance, essentially
the same as one dimensional REMD. However, in multidimensional REMD a
significantly higher number of replicas is required as the number of replicas
scales geometrically with the number of dimensions, which requires additional
computational resources. In addition to the pH dependence on standard redox
potential values and the redox potential dependence on pKa values,we also
investigate the influence of the temperature in our results. We observe an
agreement between our computational results and theoretical predictions.
