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Predicting Relative Binding Affinity Using Nonequilibrium QM/MM Simulations
journal contribution
posted on 2018-10-26, 00:00 authored by Meiting Wang, Ye Mei, Ulf RydeCalculating
binding free energies with quantum-mechanical (QM)
methods is notoriously time-consuming. In this work, we studied whether
such calculations can be accelerated by using nonequilibrium (NE)
molecular dynamics simulations employing Jarzynski’s equality.
We studied the binding of nine cyclic carboxylate ligands to the octa-acid
deep-cavity host from the SAMPL4 challenge with the reference potential
approach. The binding free energies were first calculated at the molecular
mechanics (MM) level with free energy perturbation using the generalized
Amber force field with restrained electrostatic potential charges
for the host and the ligands. Then the free energy corrections for
going from the MM Hamiltonian to a hybrid QM/MM Hamiltonian were estimated
by averaging over many short NE molecular dynamics simulations. In
the QM/MM calculations, the ligand was described at the semiempirical
PM6-DH+ level. We show that this approach yields MM → QM/MM
free energy corrections that agree with those from other approaches
within statistical uncertainties. The desired precision can be obtained
by running a proper number of independent NE simulations. For the
systems studied in this work, a total simulation length of 20 ps was
appropriate for most of the ligands, and 36–324 simulations
were necessary in order to reach a precision of 0.3 kJ/mol.