%0 Journal Article %1 Plattner2015ConformationalBindingPlasticity %A Plattner, Nuria %A Noe, Frank %D 2015 %I Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. %J Nature Communications %K computational-biology ligand-binding ligand-binding-conformational-change %T Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models %U http://dx.doi.org/10.1038/ncomms8653 %V 6 %X Understanding the structural mechanisms of protein-ligand binding and their dependence on protein sequence and conformation is of fundamental importance for biomedical research. Here we investigate the interplay of conformational change and ligand-binding kinetics for the serine protease Trypsin and its competitive inhibitor Benzamidine with an extensive set of 150thinspμs molecular dynamics simulation data, analysed using a Markov state model. Seven metastable conformations with different binding pocket structures are found that interconvert at timescales of tens of microseconds. These conformations differ in their substrate-binding affinities and binding/dissociation rates. For each metastable state, corresponding solved structures of Trypsin mutants or similar serine proteases are contained in the protein data bank. Thus, our wild-type simulations explore a space of conformations that can be individually stabilized by adding ligands or making suitable changes in protein sequence. These findings provide direct evidence of conformational plasticity in receptors.

@article{Plattner2015ConformationalBindingPlasticity, abstract = {Understanding the structural mechanisms of protein-ligand binding and their dependence on protein sequence and conformation is of fundamental importance for biomedical research. Here we investigate the interplay of conformational change and ligand-binding kinetics for the serine protease Trypsin and its competitive inhibitor Benzamidine with an extensive set of 150[thinsp]μs molecular dynamics simulation data, analysed using a Markov state model. Seven metastable conformations with different binding pocket structures are found that interconvert at timescales of tens of microseconds. These conformations differ in their substrate-binding affinities and binding/dissociation rates. For each metastable state, corresponding solved structures of Trypsin mutants or similar serine proteases are contained in the protein data bank. Thus, our wild-type simulations explore a space of conformations that can be individually stabilized by adding ligands or making suitable changes in protein sequence. These findings provide direct evidence of conformational plasticity in receptors.}, added-at = {2016-04-21T00:47:55.000+0200}, author = {Plattner, Nuria and Noe, Frank}, biburl = {https://www.bibsonomy.org/bibtex/2d38f89b2590b043dadcd98eb3cddf909/salotz}, comment = {Supplementary information available for this article at http://www.nature.com/ncomms/2015/150702/ncomms8653/suppinfo/ncomms8653_S1.html}, description = {Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models : Nature Communications : Nature Publishing Group}, interhash = {122a52d6c5fb99cd30e9dd4f7280999d}, intrahash = {d38f89b2590b043dadcd98eb3cddf909}, journal = {Nature Communications}, keywords = {computational-biology ligand-binding ligand-binding-conformational-change}, month = jul, publisher = {Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.}, timestamp = {2017-12-21T22:15:06.000+0100}, title = {Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models}, url = {http://dx.doi.org/10.1038/ncomms8653}, volume = 6, year = 2015 }