Crystal Structure of a Ten-Amino Acid Protein

Honda, Shinya; Akiba, T.; Kato, Yusuke; Sawada, Yoshito; Sekijima, Masakazu; Ishimura, Miyuki; Ooishi, Ayako; Watanabe, Hideki; Odahara, Takayuki; Harata, Kazuaki

doi:10.1021/ja8030533

Cited by 175 publications

(348 citation statements)

References 22 publications

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“…The advantage of studying chignolin is that its experimental structure is known (30) and it has been simulated for 100 μs using a special purpose machine (1), in addition to many other simulation studies (e.g., refs. [31][32][33], which provides us with good reference data.…”

Section: Algorithmmentioning

confidence: 99%

Enhanced, targeted sampling of high-dimensional free-energy landscapes using variationally enhanced sampling, with an application to chignolin

Shaffer

Valsson

Parrinello

2016

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

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The capabilities of molecular simulations have been greatly extended by a number of widely used enhanced sampling methods that facilitate escaping from metastable states and crossing large barriers. Despite these developments there are still many problems which remain out of reach for these methods which has led to a vigorous effort in this area. One of the most important problems that remains unsolved is sampling high-dimensional free-energy landscapes and systems that are not easily described by a small number of collective variables. In this work we demonstrate a new way to compute freeenergy landscapes of high dimensionality based on the previously introduced variationally enhanced sampling, and we apply it to the miniprotein chignolin.enhanced sampling | protein folding | free-energy calculation | biomolecular simulation M olecular simulation has become an increasingly useful tool for studying complex transformations in chemistry, biology, and materials science. Such simulations provide extremely high spatial and temporal resolution but suffer from inherent time-scale limitations. Molecular dynamics simulations of biomolecules performed on standard hardware struggle to exceed the microsecond time scale. Modern, purpose-built hardware can reach the millisecond time scale (1), but these tools are not generally available and they still prove insufficient for many important problems (2). Widely used enhanced sampling methods also allow one to simulate processes with a time scale of milliseconds (3) and there is significant interest in extending these methods. One important class of enhanced sampling methods involves applying an external bias to one or more collective variables (CVs) of the system. Umbrella sampling and metadynamics fall into this category (4, 5), but there are many other examples (6-13). These methods are most effective when the transformations of interest are in some sense collective and can be described by a very small number of CVs.When the choice of CV is not obvious or the free-energy landscape cannot be projected meaningfully on a low-dimensional manifold, new strategies are needed. Here we describe an enhanced sampling strategy that allows one to bias high-dimensional freeenergy landscapes by exploiting the flexibility inherent in the recently introduced variationally enhanced sampling (VES) method (14). This method casts free-energy computation as a functional minimization problem, and it solves two important problems associated with high-dimensional free-energy computation. The first problem is that when exploring a high-dimensional space a system might never visit the regions of interest, but the variational principle introduced in ref. 14 permits us to specifically target the region we are interested in through the use of a so-called "target distribution." The second problem is that one must adopt an approximation for the high-dimensional bias and the variational principle allows us to do this in an optimal way. Furthermore, as we show here, for the first time to our knowledge, choos...

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Section: Algorithmmentioning

confidence: 99%

Enhanced, targeted sampling of high-dimensional free-energy landscapes using variationally enhanced sampling, with an application to chignolin

Shaffer

Valsson

Parrinello

2016

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

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“…Honda et al (2008) obtained the crystal structure of a b-hairpin miniature protein, termed CLN025, which is a synthetic molecule consisting of 10 naturally occurring amino acids. The linear sequence of amino acids of CLN025 is Tyr1-Tyr2-Asp3-Pro4-Glu5-Thr6-Gly7-Thr8-Trp9-Tyr10 (see Fig.…”

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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“…In a previous experiment, Honda et al 39 have studied the NMR spectra of CLN025 in solution and have identified the hydrogen bonds observed in the NMR structures. In Table I, we evaluated the conformational sampling efficiency of the hybrid ICMD method by calculating the percentage of the snapshots in the simulations that have the hydrogen bond distances observed in the NMR structures within a standard deviation of the mean distance reported.…”

Section: Resultsmentioning

confidence: 99%

“…In this section, we apply the hybrid ICMD method to simulate a ten amino acid peptide CLN025 (Figure 11) for which there is an ensemble of NMR structures available. 39 Additionally, there are NMR data on the possible hydrogen bonds present in this system. We compared the conformation sampling thus obtained in FIXMAN and hybrid ICMD simulations to experimental data obtained from NMR studies as well as to the conformational sampling in FLEXIBLE simulations.…”

Section: Application Of Hybrid Icmd To Longer Peptide Chainsmentioning

confidence: 99%

Overcoming potential energy distortions in constrained internal coordinate molecular dynamics simulations

Kandel

Salomón-Ferrer

Larsen

et al. 2016

The Journal of Chemical Physics

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The Internal Coordinate Molecular Dynamics (ICMD) method is an attractive molecular dynamics (MD) method for studying the dynamics of bonded systems such as proteins and polymers. It offers a simple venue for coarsening the dynamics model of a system at multiple hierarchical levels. For example, large scale protein dynamics can be studied using torsional dynamics, where large domains or helical structures can be treated as rigid bodies and the loops connecting them as flexible torsions. ICMD with such a dynamic model of the protein, combined with enhanced conformational sampling method such as temperature replica exchange, allows the sampling of large scale domain motion involving high energy barrier transitions. Once these large scale conformational transitions are sampled, all-torsion, or even all-atom, MD simulations can be carried out for the low energy conformations sampled via coarse grained ICMD to calculate the energetics of distinct conformations. Such hierarchical MD simulations can be carried out with standard all-atom forcefields without the need for compromising on the accuracy of the forces. Using constraints to treat bond lengths and bond angles as rigid can, however, distort the potential energy landscape of the system and reduce the number of dihedral transitions as well as conformational sampling. We present here a two-part solution to overcome such distortions of the potential energy landscape with ICMD models. To alleviate the intrinsic distortion that stems from the reduced phase space in torsional MD, we use the Fixman compensating potential. To additionally alleviate the extrinsic distortion that arises from the coupling between the dihedral angles and bond angles within a force field, we propose a hybrid ICMD method that allows the selective relaxing of bond angles. This hybrid ICMD method bridges the gap between all-atom MD and torsional MD. We demonstrate with examples that these methods together offer a solution to eliminate the potential energy distortions encountered in constrained ICMD simulations of peptide molecules. C 2016 AIP Publishing LLC. [http://dx

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Crystal Structure of a Ten-Amino Acid Protein

Cited by 175 publications

References 22 publications

Enhanced, targeted sampling of high-dimensional free-energy landscapes using variationally enhanced sampling, with an application to chignolin

Enhanced, targeted sampling of high-dimensional free-energy landscapes using variationally enhanced sampling, with an application to chignolin

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

Overcoming potential energy distortions in constrained internal coordinate molecular dynamics simulations

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