  Coarse-graining of fully atomistic molecular dynamics simulations is a
long-standing goal in order to allow the description of processes occurring on
biologically relevant timescales. For example, the prediction of pathways,
rates and rate-limiting steps in protein-ligand unbinding is crucial for modern
drug discovery. To achieve the enhanced sampling, we first perform
dissipation-corrected targeted molecular dynamics simulations, which yield free
energy and friction profiles of the molecular process under consideration. In a
second step, we use these fields to perform temperature-boosted Langevin
simulations which account for the desired molecular kinetics occurring on
multisecond timescales and beyond. Adopting the dissociation of solvated sodium
chloride as well as trypsin-benzamidine and Hsp90-inhibitor protein-ligand
complexes as test problems, we are able to reproduce rates from molecular
dynamics simulation and experiments within a factor of 2-20, and dissociation
constants within a factor of 1-4. Analysis of the friction profiles reveals
that binding and unbinding dynamics are mediated by changes of the surrounding
hydration shells in all investigated systems.
