BAR-Based Multi-Dimensional Nonequilibrium Pulling for Indirect Construction of QM/MM Free Energy Landscape
2019
Construction
of free energy landscapes at Quantum mechanics (QM) level is computationally
demanding. As shown in previous studies, by employing an indirect scheme (i.e. constructing
a thermodynamic cycle connecting QM states via an alchemical pathway), simulations
are converged with much less computational burden. The indirect scheme makes
QM/ molecular mechanics (MM) free energy simulation orders of magnitude faster
than the direct QM/MM schemes. However, the indirect QM/MM simulations were
mostly equilibrium sampling based and the nonequilibrium methods were merely
exploited in one-dimensional alchemical QM/MM end-state correction at two end
states. In this work, we represent a multi-dimensional nonequilibrium pulling scheme
for indirect QM/MM free energy simulations, where the whole free energy
simulation is performed only with nonequilibrium methods. The collective
variable (CV) space we explore is a combination of one alchemical CV and one
physically meaningful CV. The current nonequilibrium indirect QM/MM simulation
method can be seen as the generalization of equilibrium perturbation based
indirect QM/MM methods. The test systems include one backbone dihedral case and
one distance case. The two cases are significantly different in size, enabling
us to investigate the dependence of the speedup of the indirect scheme on the
size of the system. It is shown that the speedup becomes larger when the size
of the system becomes larger, which is consistent with the scaling behavior of
QM Hamiltonians.
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