Long‐Time Protein Folding Dynamics from Short‐Time Molecular Dynamics Simulations

Chodera, John D.; Swope, William C.; Pitera, Jed W.; Dill, Ken A.

doi:10.1137/06065146x

Cited by 221 publications

(298 citation statements)

References 48 publications

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“…46 REMD enhances sampling by allowing configurations to heat up and cool down while maintaining proper Boltzmann distributions, in effect letting a conformational search process at higher temperatures inform that at lower ones. Each of our REMD simulations consisted of 20 replicas with temperatures exponentially spaced between 270 and 700 K. We used an implementation similar to that described in ref 47 . All trajectories were generated using the sander program in the AMBER 9 package, while replica swaps and information collection was managed by a custom Python wrapper.…”

Section: Methodsmentioning

confidence: 99%

A Test on Peptide Stability of AMBER Force Fields with Implicit Solvation

2008

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We used replica exchange molecular dynamics (REMD) simulations to evaluate four different AMBER force fields and three different implicit solvent models. Our aim was to determine if these physics-based models captured the correct secondary structures of two α-helical and two β-peptides: the 14-mer EK helix of Baldwin and co-workers, the C-terminal helix of ribonuclease, the 16-mer C-terminal hairpin of protein G, and the trpzip2 miniprotein. The different models gave different results, but generally we found that AMBER ff96 plus the implicit solvent model of Onufriev, Bashford, and Case gave reasonable structures, and is fairly well-balanced between helix and sheet. We also observed differences in the strength of ion pairing in the solvent models, we but found that the native secondary structures were retained even when salt bridges were prevented in the conformational sampling. Overall, this work indicates that some of these all-atom physics-based force fields may be good starting points for protein folding and protein structure prediction. I. Are Physics-Based Force Fields Accurate Enough for Protein Structure Predictions?All-atom force fields, such as CHARMM, 1 AMBER, 2,3 and OPLS, 4 are widely used for computer simulations of the properties of proteins and small peptides. However, such force fields are not yet commonly used to predict native protein structures, in part because of computational limitations in the conformational sampling of systems with many degrees of freedom, as in proteins, but also in part because of concerns that the force fields themselves might not be good enough. It has been difficult to distinguish whether physics-based protein structure prediction has been hindered by insufficient sampling or by limitations in the force fields.However, a few tests on protein structure prediction have been possible so far because of mechanistically focused sampling or large dedicated computer resources. There are some notable successes indicating that modern physics-based force fields might be accurate enough to predict the native structures of proteins. Using supercomputer resources, Duan and Kollman performed a milestone microsecond molecular dynamics simulation of the 36-residue villin *Corresponding author. E-mail: E-mail: shell@engineering.ucsb.edu. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript headpiece in explicit solvent starting from an unfolded conformation. 5 Scheraga's group, starting from a random configuration, folded the 46-residue protein A to within 3.5 Å rootmean-square deviation (rmsd) using Monte Carlo dynamics with an implicit solvation model. 6 Another milestone was the folding of villin by the Pande group on Folding@Home, a distributed grid computing system running on the screen savers of volunteer computers worldwide. 7Recently, higher accuracies have also been achieved. High-resolution structures of villin have recently been reached by Pande et al. 8 and Duan et al. 9,10 In addition, three groups have folded the 20-residue...

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Section: Methodsmentioning

confidence: 99%

A Test on Peptide Stability of AMBER Force Fields with Implicit Solvation

2008

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“…38 This avoids possible artifacts due to the mixing of overall rotation and internal motion, which may occur when a PCA using Cartesian coordinates is employed to study large amplitude processes such as folding. 39 As the terminal ends exhibit largely uncorrelated fluctuations, we restricted the analysis to residues 3-7 of Aib 9 . In the dLE model described below, we take into account the first five principal components (PCs), which describe the slowest timescales of Aib 9 and cover ≈80% of the total fluctuations.…”

Section: B Dimensionality Reductionmentioning

confidence: 99%

“…[8][9][10][11][12][13][14][15][16] This is achieved by partitioning the continuous MD a) Present address: Biozentrum, University of Basel and Swiss Institute of Bioinformatics, Basel, Switzerland. b) A. Rzepiela and N. Schaudinnus contributed equally to this work.…”

Section: Introductionmentioning

confidence: 99%

“…Showing a number of transition pathways with various metastable conformational states, the system exhibits complex hierarchical structural dynamics, 27 which is nontrivial to reproduce by a low-dimensional dynamical model. To generate the starting conditions for the short trajectories, we first use statistically independent points of a previously performed 4 µs MD run of Aib 9 . Alternatively, initial conditions may be generated by some enhanced sampling technique such as, for example, replica exchange methods or metadynamics.…”

Section: Introductionmentioning

confidence: 99%

“…Since a single sufficiently long MD run still represents a considerable computational challenge, 7 it would be advantageous to achieve the sampling via many short trajectories which can be run in parallel. [8][9][10][11] As a short trajectory can cover only a small part of the conformational space encountered by the system, one needs to invoke an interpolation scheme.…”

Section: Introductionmentioning

confidence: 99%

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Communication: Microsecond peptide dynamics from nanosecond trajectories: A Langevin approach

Rzepiela

Schaudinnus

Buchenberg

et al. 2014

The Journal of Chemical Physics

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Based on a given time series, the data-driven Langevin equation (dLE) estimates the drift and the diffusion field of the dynamics, which are then employed to reproduce the essential statistical and dynamical features of the original time series. Because the propagation of the dLE requires only local information, the input data are neither required to be Boltzmann weighted nor to be a continuous trajectory. Similar to a Markov state model, the dLE approach therefore holds the promise of predicting the long-time dynamics of a biomolecular system from relatively short trajectories which can be run in parallel. The practical applicability of the approach is shown to be mainly limited by the initial sampling of the system's conformational space obtained from the short trajectories. Adopting extensive molecular dynamics simulations of the unfolding and refolding of a short peptide helix, it is shown that the dLE approach is able to describe microsecond conformational dynamics from a few hundred nanosecond trajectories. In particular, the dLE quantitatively reproduces the free energy landscape and the associated conformational dynamics along the chosen five-dimensional reaction coordinate. C 2014 AIP Publishing LLC. [http://dx

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Multivalenz als chemisches Organisations‐ und Wirkprinzip

et al. 2012

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Multivalente Wechselwirkungen können universell zur gezielten Bindungsverstärkung zwischen verschiedenen Grenzflächen oder Molekülen genutzt werden. Die Bindungspartner bilden dabei kooperativ multiple Rezeptor‐Ligand‐Wechselwirkungen, die auf einzelnen schwachen, nichtkovalenten Bindungen basieren und daher prinzipiell reversibel sind. Daher spielen multi‐ und polyvalente Wechselwirkungen in biologischen Systemen eine entscheidende Rolle für Erkennungs‐, Adhäsions‐ und Signalprozesse. Die wissenschaftliche und praktische Etablierung dieses Prinzips wird anhand der Entwicklung von natürlichen Systemen über einfache artifizielle und theoretische Modelle hin zu anwendungsorientierten funktionalen Systemen demonstriert. Anhand eines systematischen Überblicks über Gerüstarchitekturen werden die zugrunde liegenden Wirk‐ und Steuerungsmöglichkeiten aufgezeigt und Designvorschläge für möglichst effektive multivalente Bindungspartner bis hin zu polyvalenten Therapeutika aufgezeigt.

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Long‐Time Protein Folding Dynamics from Short‐Time Molecular Dynamics Simulations

Cited by 221 publications

References 48 publications

A Test on Peptide Stability of AMBER Force Fields with Implicit Solvation

A Test on Peptide Stability of AMBER Force Fields with Implicit Solvation

Communication: Microsecond peptide dynamics from nanosecond trajectories: A Langevin approach

Multivalenz als chemisches Organisations‐ und Wirkprinzip

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