Molecular Simulation of ab Initio Protein Folding for a Millisecond Folder NTL9(1-39)

Department of Chemistry, Stanford University, Stanford, California 94305, USA.
Journal of the American Chemical Society (Impact Factor: 12.11). 02/2010; 132(5):1526-8. DOI: 10.1021/ja9090353
Source: PubMed


To date, the slowest-folding proteins folded ab initio by all-atom molecular dynamics simulations have had folding times in the range of nanoseconds to microseconds. We report simulations of several folding trajectories of NTL9(1-39), a protein which has a folding time of approximately 1.5 ms. Distributed molecular dynamics simulations in implicit solvent on GPU processors were used to generate ensembles of trajectories out to approximately 40 micros for several temperatures and starting states. At a temperature less than the melting point of the force field, we observe a small number of productive folding events, consistent with predictions from a model of parallel uncoupled two-state simulations. The posterior distribution of the folding rate predicted from the data agrees well with the experimental folding rate (approximately 640/s). Markov State Models (MSMs) built from the data show a gap in the implied time scales indicative of two-state folding and heterogeneous pathways connecting diffuse mesoscopic substates. Structural analysis of the 14 out of 2000 macrostates transited by the top 10 folding pathways reveals that native-like pairing between strands 1 and 2 only occurs for macrostates with p(fold) > 0.5, suggesting beta(12) hairpin formation may be rate-limiting. We believe that using simulation data such as these to seed adaptive resampling simulations will be a promising new method for achieving statistically converged descriptions of folding landscapes at longer time scales than ever before.

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    • "With regard to time, MD simulations have fundamental time scales associated with atomic vibration periods (∼ 10 −13 s), but typical MD time steps are two orders of magnitude smaller. The longest times that have been achieved in large scale MD simulations on special purpose hardware is ∼ 10 −3 s, [30]. More typically MD simulations access times of less than than 10 −8 s. "
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    • "A promising approach to model such an intricate coupling is Markov state modeling of molecular dynamics simulations [55] [56] [57] [58] [59] [60]. Such Markov state modeling has been previously applied to obtain pathways for the conformational changes of proteins [61] [62] [63] [64]. Other methods to explore rare conformational transitions of proteins with atomistic molecular dynamic simulations identify reaction coordinates or collective variables for such transitions [65] [66] [67] [68] [69]. "
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    ABSTRACT: Protein binding and function often involves conformational changes. Advanced NMR experiments indicate that these conformational changes can occur in the absence of ligand molecules (or with bound ligands), and that the ligands may ‘select’ protein conformations for binding (or unbinding). In this review, we argue that this conformational selection requires transition times for ligand binding and unbinding that are small compared to the dwell times of proteins in different conformations, which is plausible for small ligand molecules. Such a separation of timescales leads to a decoupling and temporal ordering of binding/unbinding events and conformational changes. We propose that conformational-selection and induced-change processes (such as induced fit) are two sides of the same coin, because the temporal ordering is reversed in binding and unbinding direction. Conformational-selection processes can be characterized by a conformational excitation that occurs prior to a binding or unbinding event, while induced-change processes exhibit a characteristic conformational relaxation that occurs after a binding or unbinding event. We discuss how the ordering of events can be determined from relaxation rates and effective on- and off-rates determined in mixing experiments, and from the conformational exchange rates measured in advanced NMR or single-molecule FRET experiments. For larger ligand molecules such as peptides, conformational changes and binding events can be intricately coupled and exhibit aspects of conformational-selection and induced-change processes in both binding and unbinding direction.
    Protein Science 11/2014; 23(11). DOI:10.1002/pro.2539 · 2.85 Impact Factor
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    • "However, protein motion simulation has always been a troublesome problem, mostly because of its high demanding computational requirements. Precise simulations based on molecular dynamics are usually limited to small molecules or to the use of supercomputers or distributed networks [1-3]. However, other procedures such as Ab initio or Rosetta methods do not provide information related to protein kinematics. "
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    BMC Bioinformatics 06/2014; 15(1):184. DOI:10.1186/1471-2105-15-184 · 2.58 Impact Factor
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