%0 Journal Article %1 Marinelli2009MultipleBiasTrajectories %A Marinelli, Fabrizio %A Pietrucci, Fabio %A Laio, Alessandro %A Piana, Stefano %D 2009 %I Public Library of Science %J PLOS Computational Biology %K enhanced-sampling molecular-dynamics parallel-trajectory %N 8 %P 1-18 %R 10.1371/journal.pcbi.1000452 %T A Kinetic Model of Trp-Cage Folding from Multiple Biased Molecular Dynamics Simulations %U https://doi.org/10.1371/journal.pcbi.1000452 %V 5 %X Author Summary Understanding the mechanism by which proteins find their folded state is a holy grail of computational biology. Accurate all-atom simulations have the potential to describe such a process in great detail, but, unfortunately, folding of most proteins takes place on a time scale that is still not accessible to routine computer simulations. We introduce here an approach that allows for constructing an accurate kinetic and thermodynamic model of folding (or other complex biological processes) using trajectories in which the process under investigation is forced to happen in a short simulation time by an appropriate external bias. An important strength of this approach is the possibility of identifying and characterizing misfolded conformations that, in some proteins, are related to important diseases. We use this method to study the folding of Trp-cage, predicting the structure of the folded state and the presence of several intermediates. We find that, surprisingly, fully unstructured “unfolded” states relax towards the folded conformation rather quickly. The slowest relaxation time of the system is instead related to the equilibration between the folded state and another compact structure that acts as a kinetic trap. Thus, the experimental folding time would be determined primarily by this process.

@article{Marinelli2009MultipleBiasTrajectories, abstract = {Author Summary Understanding the mechanism by which proteins find their folded state is a holy grail of computational biology. Accurate all-atom simulations have the potential to describe such a process in great detail, but, unfortunately, folding of most proteins takes place on a time scale that is still not accessible to routine computer simulations. We introduce here an approach that allows for constructing an accurate kinetic and thermodynamic model of folding (or other complex biological processes) using trajectories in which the process under investigation is forced to happen in a short simulation time by an appropriate external bias. An important strength of this approach is the possibility of identifying and characterizing misfolded conformations that, in some proteins, are related to important diseases. We use this method to study the folding of Trp-cage, predicting the structure of the folded state and the presence of several intermediates. We find that, surprisingly, fully unstructured “unfolded” states relax towards the folded conformation rather quickly. The slowest relaxation time of the system is instead related to the equilibration between the folded state and another compact structure that acts as a kinetic trap. Thus, the experimental folding time would be determined primarily by this process.}, added-at = {2017-05-03T04:33:10.000+0200}, author = {Marinelli, Fabrizio and Pietrucci, Fabio and Laio, Alessandro and Piana, Stefano}, biburl = {https://www.bibsonomy.org/bibtex/299abdfa54db9b2a94f50878f1a7b0a1f/salotz}, description = {A Kinetic Model of Trp-Cage Folding from Multiple Biased Molecular Dynamics Simulations}, doi = {10.1371/journal.pcbi.1000452}, interhash = {1f6e5fda53513cef4778965eabd44977}, intrahash = {99abdfa54db9b2a94f50878f1a7b0a1f}, journal = {PLOS Computational Biology}, keywords = {enhanced-sampling molecular-dynamics parallel-trajectory}, month = {08}, number = 8, pages = {1-18}, publisher = {Public Library of Science}, timestamp = {2017-05-03T04:33:10.000+0200}, title = {A Kinetic Model of Trp-Cage Folding from Multiple Biased Molecular Dynamics Simulations}, url = {https://doi.org/10.1371/journal.pcbi.1000452}, volume = 5, year = 2009 }