Equilibration of Protein States: A Time Dependent Free-Energy Disconnectivity Graph

Chekmarev, S. F.

doi:10.1021/acs.jpcb.5b04336

Cited by 2 publications

(1 citation statement)

References 53 publications

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“…Since some initial clusters fell into the same basins on the FES, all initial clusters were grouped into "consolidated clusters", taking into account the proximity of the initial clusters in the (g 1 , g 2 ) space and their kinetic connectivity [40]. To determine cluster connectivity, free energy disconnectivity graphs [58] were used, which separated the initial clusters into consolidated clusters such that the free energy barriers between the consolidated clusters were considerably higher than the barriers between the initial clusters within the consolidated clusters (Supporting Information, Figs. S4, S5, and S6).…”

Section: System and Methodsmentioning

confidence: 99%

Temperature evolution of Trp-cage folding pathways: An analysis by dividing the probability flux field into stream tubes

Andryushchenko

Chekmarev

2017

J Biol Phys

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Owing to its small size and very fast folding rate, the Trp-cage miniprotein has become a benchmark system to study protein folding. Two folding pathways were found to be characteristic of this protein: pathway I, in which the hydrophobic collapse precedes the formation of α-helix, and pathway II, in which the events occur in the reverse order. At the same time, the relative contribution of these pathways at different temperatures as well as the nature of transition from one pathway to the other remain unclear. To gain insight into this issue, we employ a recently proposed hydrodynamic description of protein folding, in which the process of folding is considered as a motion of a "folding fluid" (Chekmarev et al., Phys. Rev. Lett. 100(1), 018107 2008). Using molecular dynamics simulations, we determine the field of probability fluxes of transitions in a space of collective variables and divide it into stream tubes. Each tube contains a definite fraction of the total folding flow and can be associated with a certain pathway. Specifically, three temperatures were considered, T = 285K, T = 315K, and T = 325K. We have found that as the temperature increases, the contribution of pathway I, which is approximately 90% of the total folding flow at T = 285K, decreases to approximately 10% at T = 325K, i.e., pathway II becomes dominant. At T = 315K, both pathways contribute approximately equally. All these temperatures are found below the calculated melting point, which suggests that the Trp-cage folding mechanism is determined by kinetic factors rather than thermodynamics.

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Section: System and Methodsmentioning

confidence: 99%

Temperature evolution of Trp-cage folding pathways: An analysis by dividing the probability flux field into stream tubes

Andryushchenko

Chekmarev

2017

J Biol Phys

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A hydrodynamic view of the first-passage folding of Trp-cage miniprotein

Andryushchenko

Chekmarev

2015

Eur Biophys J

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We study folding of Trp-cage miniprotein in the conditions when the native state of the protein is stable and unfolding events are improbable, which corresponds to physiological conditions. Using molecular dynamics simulations with an implicit solvent model, an ensemble of folding trajectories from unfolded (practically extended) states of the protein to the native state was generated. To get insight into the folding kinetics, the free energy surface and kinetic network projected on this surface were constructed. This, "conventional" analysis of the folding reaction was followed by a recently proposed hydrodynamic description of protein folding (Chekmarev et al. in Phys Rev Lett 100(1):018107, 2008), in which the process of the first-passage folding is viewed as a stationary flow of a folding "fluid" from the unfolded to native state. This approach is conceptually different from the previously used approaches and thus allows an alternative view of the folding dynamics and kinetics of Trp-cage, the conclusions about which are very diverse. In agreement with most previous studies, we observed two characteristic folding pathways: in one pathway (I), the collapse of the hydrophobic core precedes the formation of the [Formula: see text]-helix, and in the other pathway (II), these events occur in the reverse order. We found that although pathway II is complicated by a repeated partial protein unfolding, it contributes to the total folding flow as little as ≈10%, so that the folding kinetics remain essentially single-exponential.

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Equilibration of Protein States: A Time Dependent Free-Energy Disconnectivity Graph

Cited by 2 publications

References 53 publications

Temperature evolution of Trp-cage folding pathways: An analysis by dividing the probability flux field into stream tubes

Temperature evolution of Trp-cage folding pathways: An analysis by dividing the probability flux field into stream tubes

A hydrodynamic view of the first-passage folding of Trp-cage miniprotein

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