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Quantitative comparison of villin headpiece subdomain simulations and triplet-triplet energy transfer experiments.

ABSTRACT: As the fastest folding protein, the villin headpiece (HP35) serves as an important bridge between simulation and experimental studies of protein folding. Despite the simplicity of this system, experiments continue to reveal a number of surprises, including structure in the unfolded state and complex equilibrium dynamics near the native state. Using 2.5 ms of molecular dynamics and Markov state models, we connect to current experimental results in three ways. First, we present and validate a novel method for the quantitative prediction of triplet-triplet energy transfer experiments. Second, we construct a many-state model for HP35 that is consistent with previous experiments. Finally, we predict contact-formation time traces for all 1,225 possible triplet-triplet energy transfer experiments on HP35.

SUBMITTER: Beauchamp KA

PROVIDER: S-EPMC3150881 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Quantitative comparison of villin headpiece subdomain simulations and triplet-triplet energy transfer experiments.

Beauchamp Kyle A KA Ensign Daniel L DL Das Rhiju R Pande Vijay S VS

Proceedings of the National Academy of Sciences of the United States of America 20110718 31

As the fastest folding protein, the villin headpiece (HP35) serves as an important bridge between simulation and experimental studies of protein folding. Despite the simplicity of this system, experiments continue to reveal a number of surprises, including structure in the unfolded state and complex equilibrium dynamics near the native state. Using 2.5 ms of molecular dynamics and Markov state models, we connect to current experimental results in three ways. First, we present and validate a nove ...[more]

PMID: 21768345

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Project description:BackgroundEstimators of free energies are routinely used to judge the quality of protein structural models. As these estimators still present inaccuracies, they are frequently evaluated by discriminating native or native-like conformations from large ensembles of so-called decoy structures.ResultsA decoy set is obtained from snapshots taken from 5 long (100 ns) molecular dynamics (MD) simulations of the thermostable subdomain from chicken villin headpiece. An evaluation of the energy of the decoys is given using: i) a residue based contact potential supplemented by a term for the quality of dihedral angles; ii) a recently introduced combination of four statistical scoring functions for model quality estimation (FRST); iii) molecular mechanics with solvation energy estimated either according to the generalized Born surface area (GBSA) or iv) the Poisson-Boltzmann surface area (PBSA) method.ConclusionThe decoy set presented here has the following features which make it attractive for testing energy scoring functions:1) it covers a broad range of RMSD values (from less than 2.0 A to more than 12 A);2) it has been obtained from molecular dynamics trajectories, starting from different non-native-like conformations which have diverse behaviour, with secondary structure elements correctly or incorrectly formed, and in one case folding to a native-like structure. This allows not only for scoring of static structures, but also for studying, using free energy estimators, the kinetics of folding;3) all structures have been obtained from accurate MD simulations in explicit solvent and after molecular mechanics (MM) energy minimization using an implicit solvent method. The quality of the covalent structure therefore does not suffer from steric or covalent problems. The statistical and physical effective energy functions tested on the set behave differently when native simulation snapshots are included or not in the set and when averaging over the trajectory is performed.

Dataset Information

Quantitative comparison of villin headpiece subdomain simulations and triplet-triplet energy transfer experiments.

Publications

Quantitative comparison of villin headpiece subdomain simulations and triplet-triplet energy transfer experiments.

Similar Datasets

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