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Predicting the complete free energy landscape associated with protein-ligand unbinding may greatly help designing drugs with highly optimized pharmacokinetics. This its very important, because one needs to know not only the affinity of a drug for its target but also how long it is bound to it. By feeding out-of-equilibrium molecular simulations data in a classification analysis, we identify the few essential reaction coordinates of ligand unbinding processes to neuroreceptors [1,2]. The full landscape is then reconstructed using an exact enhanced sampling method, like the well-tempered metadynamics. Finally, to predict koff of ligands to proteins, we use a recently proposed method by Prof. Michele Parrinello and co-workers to evaluate the koff of a molecule binding to a protein. This work is funded by the European Human Brain Project and is in collaboration with Prof. Michele Parrinello.


  1. Casasnovas R,  Limongelli V, Tiwary P, Carloni P, Parrinello M (2017) Unbinding Kinetics of a p38 MAP Kinase Type II Inhibitor from Metadynamics Simulations. J. Am. Che. Soc. 139(13): p. 4780-4788. doi: 10.1021/jacs.6b12950
  2. Capelli R, Bochicchio A, Piccini G, Casasnovas R, Carloni P, Parrinello M (2019) Chasing the Full Free Energy Landscape of Neuroreceptor/Ligand Unbinding by Metadynamics Simulations. J Chem Theory Comput. 15(5): p. 3354-3361. doi: 10.1021/acs.jctc.9b00118