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 necessary for coarse-graining , 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  Langevin simulations which account for the desired molecular kinetics . By introducing the concept of 'temperature boosting' of the Langevin simulations, this combination of methods allows simulation of biomolecular processes 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 the rates from atomistic molecular dynamics simulation and experiments within a factor of 1.5-4 for unbinding times up to the range of milliseconds and of 1.2-10 in the range of seconds . Analysis of the friction profiles reveals that binding and unbinding dynamics are mediated by changes of the surrounding hydration shells in all investigated systems.
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.
D
necessary for coarse-graining
A
temperature-boosted
D
. By introducing the concept of 'temperature boosting' of the Langevin simulations, this combination of methods allows simulation of biomolecular processes
R
the rates from atomistic
rates from
R
1.5-4 for unbinding times up to the range of milliseconds and of 1.2-10 in the range of seconds
2-20, and dissociation constants within a factor of 1-4