Alchemical transformation in ORAC can be effectively used for the
determination of ligand-receptor binding free energies via the
so-called Fast switching Double Annihilation method
(FS-DAM).[1] In this approach, ORAC can be used to produce
simultaneously in a parallel application many fast and independent
non-equilibrium Molecular Dynamics trajectories with a continuous
dynamical evolution of an externally driven alchemical coordinate,
completing the decoupling of the ligand in a matter of few tens of
picoseconds rather than nanoseconds. In FS-DAM, the requirement of an
equilibrium transformation along the entire alchemical path, that is
the major stumbling block in obtaining reliable (converged) free
energy values via the standard equilibrium approach based on free
energy perturbation (FEP/REST),[156] is lifted altogether
and the drug-receptor absolute binding free energy can be recovered
with reliability from the parallel computation of the annihilation
work distribution. To the latter, a unidirectional free energy
estimate can be applied, on the assumption that any observed non
equilibrium work distribution is given by a mixture of normal
distributions, whose components are identical in either direction of
the non-equilibrium process, with weights regulated by the Crooks
theorem.[157] In contrast to the FEP/REST approach based
on the equilibrium simulations of many intermediate alchemical states,
in FS-DAM, the equilibrium sampling is required only at the starting
fully coupled states (easily attainable using conventional enhanced
sampling simulation methods).
procacci
2021-12-29
