Raw data of molecular dynamics simulations of rat phenylalanine hydroxylase (T22-K450) tetramer. Missing residues were rebuilt using Modeller. Metal site was parameterized using MCPB.py in AmberTools. Simulation starts from the crystal pose (PDB: 5DEN).
Raw REMD simulation data (protein only) of designed β-hairpins. AMBER ff99SB-ildn and implicit solvent model is used. More details can be found in this paper: Yunhui Ge, Brandon Kier, Niels H. Andersen and Vincent A. Voelz. Computational and experimental evaluation of designed beta-cap hairpins using molecular simulations and kinetic network models. J. Chem. Inf. Model., 2017, 57 (7), pp 1609–1620
Raw data of molecular dynamics simulations of regulatory ACT domain dimer mutation (K42I). binding.zip: simulation of dimer with 19 Phe ligand bound.zip: simulation of dimer with bound Phe ligand dimer.zip: simulation of dimer only Simulation setup files are also included in each folder.
Protein folding is a fundamental process in biology, key to understanding many human diseases. Experimentally, proteins often appear to fold via simple two- or three-state mechanisms involving mainly native-state interactions, yet recent network models built from atomistic simulations of small proteins suggest the existence of many possible metastable states and folding pathways. We reconcile these two pictures in a combined experimental and simulation study of acyl-coenzyme A binding protein (ACBP), a two-state folder (folding time ~10 ms) exhibiting residual unfolded-state structure, and a putative early folding intermediate. Using single-molecule FRET in conjunction with side-chain mutagenesis, we first demonstrate that the denatured state of ACBP at near-zero denaturant is unusually compact and enriched in long-range structure that can be perturbed by discrete hydrophobic core mutations. We then employ ultrafast laminar-flow mixing experiments to study the folding kinetics of ACBP on the microsecond time scale. These studies, along with Trp-Cys quenching measurements of unfolded-state dynamics, suggest that unfolded-state structure forms on a surprisingly slow (~100 μs) time scale, and that sequence mutations strikingly perturb both time-resolved and equilibrium smFRET measurements in a similar way. A Markov state model (MSM) of the ACBP folding reaction, constructed from over 30 ms of molecular dynamics trajectory data, predicts a complex network of metastable stables, residual unfolded-state structure, and kinetics consistent with experiment but no well-defined intermediate preceding the main folding barrier. Taken together, these experimental and simulation results suggest that the previously characterized fast kinetic phase is not due to formation of a barrier-limited intermediate but rather to a more heterogeneous and slow acquisition of unfolded-state structure.
Raw data of molecular dynamics simulations of regulatory ACT domain monomer mutation (T63P). Simulation setup files are also included. 21 starting conformations are used in simulations.
Raw data of molecular dynamics simulations of regulatory ACT domain dimer mutation (I65S). binding.zip: simulation of dimer with 19 Phe ligand bound.zip: simulation of dimer with bound Phe ligand dimer.zip: simulation of dimer only Simulation setup files are also included in each folder.
Author(s): Voelz, Vincent Alvin | Advisor(s): Dill, Ken A | Abstract: We currently have a great deal of experimental data about how particular proteins fold, but no description of protein folding that could be used as a recipe to fold proteins. Here, we explore a model of protein folding called Zipping and Assembly (ZaA). Zipping refers to the growth of topologically local substructures within the chain, and assembly refers to the coming together of already-formed pieces.We first trace the development of our theoretical understanding of protein folding, and discuss what the current state of experiments and theory tell us about the prospect of developing a recipe for protein folding. In particular, we explain the need for a folding principle, a microscopic description of folding that could be used to predict the folding pathways and native state of an arbitrary sequence of amino acids.To determine whether ZaA is a general method that can efficiently fold most of sequence space to global minima, we use the HP model, with which it is possible to enumerate full conformation and sequence spaces. We find that ZaA reaches the global energy minimum native states, even though it searches only a very small fraction of conformational space, for most sequences in the full sequence space. Furthermore, a ZaA-based search recapitulates key features of protein folding such as topology-dependent folding rates and characteristic early-vs.-late assemblies.With the aim of putting the principles of ZaA to practice in an automated algorithm that works with atomically-detailed molecular mechanics models of proteins, we analyze a set of contact metrics extracted from a large database of short REMD simulations of peptide fragments. By building optimal Bayesian classification models, we show that it is possible to achieve up to 27% classification success in predicting native and non-native contacts from short fragment simulations. The most informative metric we tested was contact probability, with much smaller effects coming from multi-body metrics. Predictions for a test protein show how the classification model helps to prioritize the search process with the Zipping and Assembly Method (ZAM).
In this work, we investigate the role of solvent in the binding reaction of the p53 transactivation domain (TAD) peptide to its receptor MDM2. Previously, our group generated 831 μs of explicit-solvent aggregate molecular simulation trajectory data for the MDM2-p53 peptide binding reaction using large-scale distributed computing and subsequently built a Markov State Model (MSM) of the binding reaction (Zhou et al. 2017). Here, we perform a tICA analysis and construct an MSM with similar hyperparameters while using only solvent-based structural features. We find a remarkably similar landscape but accelerated implied timescales for the slowest motions. The solvent shells contributing most to the first tICA eigenvector are those centered on Lys24 and Thr18 of the p53 TAD peptide in the range of 3–6 Å. Important solvent shells were visualized to reveal solvation and desolvation transitions along the peptide–protein binding trajectories. Our results provide a solvent-centric view of the hydrophobic effect in action for a realistic peptide–protein binding scenario.
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