Obtaining atomistic resolution of drug unbinding from a protein is a much sought-after experimental and computational challenge. We report the unbinding dynamics of the anticancer drug dasatinib from c-Src kinase in full atomistic resolution using enhanced sampling molecular dynamics simulations. We obtain multiple unbinding trajectories and determine a residence time in agreement with experiments. We observe coupled protein-water movement through multiple metastable intermediates. The water molecules form a hydrogen bond bridge, elongating a specific, evolutionarily preserved salt bridge and enabling conformation changes essential to ligand unbinding. This water insertion in the salt bridge acts as a molecular switch that controls unbinding. Our findings provide a mechanistic rationale for why it might be difficult to engineer drugs targeting certain specific c-Src kinase conformations to have longer residence times.
%0 Journal Article
%1 Tiwary2017DasatinibUnbinding
%A Tiwary, Pratyush
%A Mondal, Jagannath
%A Berne, B. J.
%D 2017
%I American Association for the Advancement of Science
%J Science Advances
%K ligand-unbinding metadynamics molecular-dynamics
%N 5
%R 10.1126/sciadv.1700014
%T How and when does an anticancer drug leave its binding site?
%U http://advances.sciencemag.org/content/3/5/e1700014
%V 3
%X Obtaining atomistic resolution of drug unbinding from a protein is a much sought-after experimental and computational challenge. We report the unbinding dynamics of the anticancer drug dasatinib from c-Src kinase in full atomistic resolution using enhanced sampling molecular dynamics simulations. We obtain multiple unbinding trajectories and determine a residence time in agreement with experiments. We observe coupled protein-water movement through multiple metastable intermediates. The water molecules form a hydrogen bond bridge, elongating a specific, evolutionarily preserved salt bridge and enabling conformation changes essential to ligand unbinding. This water insertion in the salt bridge acts as a molecular switch that controls unbinding. Our findings provide a mechanistic rationale for why it might be difficult to engineer drugs targeting certain specific c-Src kinase conformations to have longer residence times.
@article{Tiwary2017DasatinibUnbinding,
abstract = {Obtaining atomistic resolution of drug unbinding from a protein is a much sought-after experimental and computational challenge. We report the unbinding dynamics of the anticancer drug dasatinib from c-Src kinase in full atomistic resolution using enhanced sampling molecular dynamics simulations. We obtain multiple unbinding trajectories and determine a residence time in agreement with experiments. We observe coupled protein-water movement through multiple metastable intermediates. The water molecules form a hydrogen bond bridge, elongating a specific, evolutionarily preserved salt bridge and enabling conformation changes essential to ligand unbinding. This water insertion in the salt bridge acts as a molecular switch that controls unbinding. Our findings provide a mechanistic rationale for why it might be difficult to engineer drugs targeting certain specific c-Src kinase conformations to have longer residence times.},
added-at = {2017-06-07T18:08:23.000+0200},
author = {Tiwary, Pratyush and Mondal, Jagannath and Berne, B. J.},
biburl = {https://www.bibsonomy.org/bibtex/238c97953349a1be1ec1c9d2a359d7541/salotz},
doi = {10.1126/sciadv.1700014},
eprint = {http://advances.sciencemag.org/content/3/5/e1700014.full.pdf},
interhash = {624b48daa79c345e810b616566741afd},
intrahash = {38c97953349a1be1ec1c9d2a359d7541},
journal = {Science Advances},
keywords = {ligand-unbinding metadynamics molecular-dynamics},
number = 5,
publisher = {American Association for the Advancement of Science},
timestamp = {2017-06-07T18:08:23.000+0200},
title = {How and when does an anticancer drug leave its binding site?},
url = {http://advances.sciencemag.org/content/3/5/e1700014},
volume = 3,
year = 2017
}