Confinement-Induced States in the Folding Landscape of the Trp-cage Miniprotein

Marino, Kristen A.; Bolhuis, Peter G.

doi:10.1021/jp306727r

Cited by 34 publications

(42 citation statements)

References 58 publications

(109 reference statements)

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“…Furthermore, these populations predict that at room temperature the fraction of unfolded to folded configuration is p U /p N ≈ 0.23, where we take the SN state to be a folded state. In a recent REMD calculation, 47 using the same force field, this fraction was predicted around 0.20, close to our current calculation. Previous measurements of the folding curve yielded p U /p N ≈ 0.33, 15 and more recent IR experiments find a p U /p N ≈ 0.2, close to our predictions.…”

Section: The Stationary Distribution or Equilibrium Populationsupporting

confidence: 90%

Sampling the equilibrium kinetic network of Trp-cage in explicit solvent

Du¹,

Bolhuis²

2014

The Journal of Chemical Physics

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We employed the single replica multiple state transition interface sampling (MSTIS) approach to sample the kinetic (un)folding network of Trp-cage mini-protein in explicit water. Cluster analysis yielded 14 important metastable states in the network. The MSTIS simulation thus resulted in a full 14 × 14 rate matrix. Analysis of the kinetic rate matrix indicates the presence of a near native intermediate state characterized by a fully formed alpha helix, a slightly disordered proline tail, a broken salt-bridge, and a rotated arginine residue. This intermediate was also found in recent IR experiments. Moreover, the predicted rate constants and timescales are in agreement with previous experiments and simulations.

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Section: The Stationary Distribution or Equilibrium Populationsupporting

confidence: 90%

Sampling the equilibrium kinetic network of Trp-cage in explicit solvent

Du¹,

Bolhuis²

2014

The Journal of Chemical Physics

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“…In addition, the abundant availability of the native states brings the observation of the existence of two substates in the native region. The molecular structures of two substates are in agreement with the previous computational 33,34 and experimental 34,35 studies. Moreover, three possible folding pathways are observed in the analyzing of C α -C α (helix) RMSD relationship, which indicates that various mechanisms might exist in the folding of trp-cage protein.…”

Section: Concluding Discussionsupporting

confidence: 89%

“…Between the two substates, the N-terminal helixes of the two structures are almost the same, and differences between the two are mainly caused by the C-terminal polyproline region. Our observation is consistent with the previous computational 33,34 and experimental 34,35 studies about the existence of these two substates.…”

Section: Small Protein Foldingsupporting

confidence: 93%

Parallel continuous simulated tempering and its applications in large-scale molecular simulations

Zang

Zhang

et al. 2014

The Journal of Chemical Physics

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In this paper, we introduce a parallel continuous simulated tempering (PCST) method for enhanced sampling in studying large complex systems. It mainly inherits the continuous simulated tempering (CST) method in our previous studies [C. Zhang and J. Ma, J. Chem. Phys. 130, 194112 (2009); 132, 244101 (2010)], while adopts the spirit of parallel tempering (PT), or replica exchange method, by employing multiple copies with different temperature distributions. Differing from conventional PT methods, despite the large stride of total temperature range, the PCST method requires very few copies of simulations, typically 2-3 copies, yet it is still capable of maintaining a high rate of exchange between neighboring copies. Furthermore, in PCST method, the size of the system does not dramatically affect the number of copy needed because the exchange rate is independent of total potential energy, thus providing an enormous advantage over conventional PT methods in studying very large systems. The sampling efficiency of PCST was tested in two-dimensional Ising model, LennardJones liquid and all-atom folding simulation of a small globular protein trp-cage in explicit solvent. The results demonstrate that the PCST method significantly improves sampling efficiency compared with other methods and it is particularly effective in simulating systems with long relaxation time or correlation time. We expect the PCST method to be a good alternative to parallel tempering methods in simulating large systems such as phase transition and dynamics of macromolecules in explicit solvent.

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“…26 Organic CH 3 SAMs appear to act as intermediate protein stabilizers between bulk and the more destabilizing graphene, whereas organic COOH SAMs reinforce the stabilized bulk state. MetaD exhibits similar RMSD trends to REMD; however, additional unfolded structures (Cα RMSD ≥ 2.2 Å) are also detected on the free-energy surface of CH 3 SAMs.…”

Section: ■ Methodsmentioning

confidence: 98%

Trp-Cage Folding on Organic Surfaces

et al. 2015

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Trp-cage is an artificial miniprotein that is small, stable, and fast folding due to concerted hydrophobic shielding of a Trp residue by polyproline helices. Simulations have extensively characterized Trp-cage; however, the interactions of Trp-cage with organic surfaces (e.g., membranes) and their effect on protein conformation are largely unknown. To better understand these interactions we utilized a combination of replica-exchange molecular dynamics (REMD) and metadynamics (MetaD), to investigate Trp-cage folding on self-assembled monolayers (SAMs). We found that, with REMD and MetaD, Trp-cage strongly binds to neutral CH3 surfaces (-25kT) and moderately adsorbs to anionic COOH interfaces (-7.6kT), with hydrophobic interactions driving CH3 adhesion and electrostatic attractions driving COOH adhesion. Similar to solid-state surfaces, SAMs facilitate a number of intermediate Trp-cage conformations between folded and unfolded states. Regarding Trp-cage's aromatic groups in neutral CH3 systems, Tyr becomes oriented parallel to the surface in order to maximize hydrophobic interactions while Trp remains caged perpendicular to the surface; however, Trp can reorient itself parallel to the interface as the miniprotein more closely binds to the surface. In contrast, Tyr and Trp are both repelled from COOH surfaces, though the Trp-cage still adheres to the anionic interface via Lys and its N-terminated Asn residue.

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Confinement-Induced States in the Folding Landscape of the Trp-cage Miniprotein

Cited by 34 publications

References 58 publications

Sampling the equilibrium kinetic network of Trp-cage in explicit solvent

Sampling the equilibrium kinetic network of Trp-cage in explicit solvent

Parallel continuous simulated tempering and its applications in large-scale molecular simulations

Trp-Cage Folding on Organic Surfaces

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