Predicting Relative Binding Affinity Using Nonequilibrium QM/MM Simulations

Meiting Wang, Ye Mei, Ulf Ryde

Research output: Contribution to journalArticlepeer-review

9 Citations (SciVal)
59 Downloads (Pure)


Calculating binding free energies with quan-
tum-mechanical (QM) methods is notoriously time-consum-
ing. 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.
Original languageEnglish
Pages (from-to)6613
Number of pages6622
JournalJournal of Chemical Theory and Computation
Publication statusPublished - 2018 Oct 26

Subject classification (UKÄ)

  • Theoretical Chemistry


Dive into the research topics of 'Predicting Relative Binding Affinity Using Nonequilibrium QM/MM Simulations'. Together they form a unique fingerprint.

Cite this