title: Unfolded-state dynamics and structure of protein L characterized by simulation and experiment.
abstract: While several experimental techniques now exist for characterizing protein unfolded states, all-atom simulation of unfolded states has been challenging due to the long time scales and conformational sampling required. We address this problem by using a combination of accelerated calculations on graphics processor units and distributed computing to simulate tens of thousands of molecular dynamics trajectories each up to approximately 10 mus (for a total aggregate simulation time of 127 ms). We used this approach in conjunction with Trp-Cys contact quenching experiments to characterize the unfolded structure and dynamics of protein L. We employed a polymer theory method to make quantitative comparisons between high-temperature simulated and chemically denatured experimental ensembles and find that reaction-limited quenching rates calculated from simulation agree remarkably well with experiment. In both experiment and simulation, we find that unfolded-state intramolecular diffusion rates are very slow compared to highly denatured chains and that a single-residue mutation can significantly alter unfolded-state dynamics and structure. This work suggests a view of the unfolded state in which surprisingly low diffusion rates could limit folding and opens the door for all-atom molecular simulation to be a useful predictive tool for characterizing protein unfolded states along with experiments that directly measure intramolecular diffusion.
authors.affiliation: Department of Chemistry, Stanford University, Stanford, California 94305, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Voelz
authors.forename: Vijay R
authors.initials: VR
authors.lastname: Singh
authors.forename: William J
authors.initials: WJ
authors.lastname: Wedemeyer
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Lapidus
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Pande
mesh_terms: D002138:Calibration; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry*; D013696:Temperature; D013816:Thermodynamics
chemical_list: D011506:Proteins