Challenges in protein-folding simulations

Freddolino, Peter L.; Harrison, Christopher B.; Liu, Yanxin; Schulten, Klaus

doi:10.1038/nphys1713

Cited by 309 publications

(277 citation statements)

References 101 publications

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“…Many of the questions that scientists actually use simulations to answer are cases that they regard as falling well enough into this category, where our beliefs about the determinants of the behavior of interest are already so well justified that doing an experiment would have no marginal benefit. A mixed example that illustrates this point, and that includes a variety of questions whose answers do and do not depend on unknown factors, is the way that simulations and experiments are used to understand the principles governing protein folding (Freddolino et al 2010;Piana et al 2011Piana et al , 2014.…”

Section: Blackboxing and Background Knowledgementioning

confidence: 99%

The epistemic superiority of experiment to simulation

Roush

2017

Synthese

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This paper defends the naïve thesis that the method of experiment has per se an epistemic superiority over the method of computer simulation, a view that has been rejected by some philosophers writing about simulation, and whose grounds have been hard to pin down by its defenders. I further argue that this superiority does not come from the experiment's object being materially similar to the target in the world that the investigator is trying to learn about, as both sides of dispute over the epistemic superiority thesis have assumed. The superiority depends on features of the question and on a property of natural kinds that has been mistaken for material similarity. Seeing this requires holding other things equal in the comparison of the two methods, thereby exposing that, under the conditions that will be specified, the simulation is necessarily epistemically one step behind the corresponding experiment. Practical constraints like feasibility and morality mean that scientists do not often face an other-things-equal comparison when they choose between experiment and simulation. Nevertheless, I argue, awareness of this superiority and of the general distinction between experiment and simulation is important for maintaining motivation to seek answers to new questions.

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Section: Blackboxing and Background Knowledgementioning

confidence: 99%

The epistemic superiority of experiment to simulation

Roush

2017

Synthese

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“…Under some conditions, such as high temperature, extremes of pH or mechanical forces, protein will unfold into random coil that loses biochemical function (Selkoe 2003). Since folding and unfolding are essential to life, literatures on the study of these processes are very rich (Gao and Truhlar 2002;Gao et al 2006;Freddolino et al 2010;Yang et al 2010;Alhambra et al 2000;Duan et al 2010;Shank et al 2010). And it has been greatly advanced in recent years by the development of fast time-resolved techniques.…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics simulation exploration of unfolding and refolding of a ten-amino acid miniprotein

Zhao

Cheng

2011

Amino Acids

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Steered molecular dynamics simulations are performed to explore the unfolding and refolding processes of CLN025, a 10-residue beta-hairpin. In unfolding process, when CLN025 is pulled along the termini, the forceextension curve goes back and forth between negative and positive values not long after the beginning of simulation. That is so different from what happens in other peptides, where force is positive most of the time. The abnormal phenomenon indicates that electrostatic interaction between the charged termini plays an important role in the stability of the beta-hairpin. In the refolding process, the collapse to beta-hairpin-like conformations is very fast, within only 3.6 ns, which is driven by hydrophobic interactions at the termini, as the hydrophobic cluster involves aromatic rings of Tyr1, Tyr2, Trp9, and Tyr10. Our simulations improve the understanding on the structure and function of this type of miniprotein and will be helpful to further investigate the unfolding and refolding of more complex proteins.

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“…Until recently, the length of such simulations was limited to a few microseconds-a timescale sufficient to capture, at best, a single folding event (8,9). With this limitation, it has been difficult to directly connect the data produced by short, non-equilibrium simulations to experimental observations, unless sufficient statistics were generated to allow the construction of coarse-grained kinetic models that approximate the underlying folding dynamics (10, 11).…”

mentioning

confidence: 99%

Protein folding kinetics and thermodynamics from atomistic simulation

Piana

Lindorff‐Larsen

Shaw

2012

Proc. Natl. Acad. Sci. U.S.A.

284

372

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Advances in simulation techniques and computing hardware have created a substantial overlap between the timescales accessible to atomic-level simulations and those on which the fastest-folding proteins fold. Here we demonstrate, using simulations of four variants of the human villin headpiece, how simulations of spontaneous folding and unfolding can provide direct access to thermodynamic and kinetic quantities such as folding rates, free energies, folding enthalpies, heat capacities, Φ-values, and temperaturejump relaxation profiles. The quantitative comparison of simulation results with various forms of experimental data probing different aspects of the folding process can facilitate robust assessment of the accuracy of the calculations while providing a detailed structural interpretation for the experimental observations. In the example studied here, the analysis of folding rates, Φ-values, and folding pathways provides support for the notion that a norleucine double mutant of villin folds five times faster than the wild-type sequence, but following a slightly different pathway. This work showcases how computer simulation has now developed into a mature tool for the quantitative computational study of protein folding and dynamics that can provide a valuable complement to experimental techniques.Amber ff99SB*-ILDN | enthalpy | heat capacity | pre-exponential factor | transition path time P roteins are synthesized in the cell or in vitro as unstructured polypeptide chains that, in most cases, self-assemble into their functionally active three-dimensional shapes. This process, called protein folding, occurs on a broad range of timescales ranging from microseconds to seconds and higher. From a purely physical-chemical perspective, it should be possible in principle to characterize the folding mechanism of a given protein at atomistic resolution and to reconstruct its free-energy landscape, given only its primary sequence, through molecular dynamics (MD) simulations based on elementary physical principles. This direct approach has been rarely pursued because even the simplest systems representing a protein immersed in water consist of several thousand atoms, and simulating their behavior on the timescales typical of protein folding is computationally extremely demanding. The discovery and design of fast-folding proteins (1) significantly narrowed the timescale gap between simulations and experiments, making such simulations feasible, at least for the fastest-folding proteins.The C-terminal fragment of the villin headpiece [referred to in the remainder of this paper simply as "villin" (2)], one of the fastest-folding protein domains known (3), has proven to be an excellent target for folding simulations with physics-based force fields and an atomistically detailed representation of both the solute and the surrounding solvent (4-7). Until recently, the length of such simulations was limited to a few microseconds-a timescale sufficient to capture, at best, a single folding event (8,9). With this limitation, it has bee...

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Challenges in protein-folding simulations

Cited by 309 publications

References 101 publications

The epistemic superiority of experiment to simulation

The epistemic superiority of experiment to simulation

Molecular dynamics simulation exploration of unfolding and refolding of a ten-amino acid miniprotein

Protein folding kinetics and thermodynamics from atomistic simulation

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