2010/03/10 by Vincent A. Voelz, Vijay Raj Singh, William J. Wedemeyer +2 · 1 citation
Biochemistry, Genetics and Molecular Biology · Materials Science · Physics and Astronomy · Chemistry · #Protein Structure and Dynamics #Enzyme Structure and Function #Spectroscopy and Quantum Chemical Studies #Chemistry #Molecular dynamics #Intramolecular force #Protein folding #Chemical physics #Quenching (fluorescence) #Unfolded protein response #Diffusion #Statistical physics #Computational chemistry #Thermodynamics #Physics
paper · doi:10.1021/ja908369h
openalex publication_date 2010/03/10 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
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.