Simulations of thermodynamics and kinetics on rough energy landscapes with milestoning

Bello-Rivas, Juan M.; Elber, Ron

doi:10.1002/jcc.24039

Cited by 15 publications

(24 citation statements)

References 27 publications

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“…We consider transitions between these compartments and will combine the information on local transitions, using consistency criterion, to obtain global information. Short trajectories (here we consider Brownian dynamics (Bello-Rivas & Elber, 2015, 2016)) are initiated on milestones and chart paths between different interfaces. The original initiating milestone can be re-crossed, and the trajectory is stopped only when it hits for the first time another milestone.…”

Section: The Use Of Short Trajectories To Simulate Long Time Kineticsmentioning

confidence: 99%

A new paradigm for atomically detailed simulations of kinetics in biophysical systems

Elber

2017

Quart. Rev. Biophys.

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112

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The kinetics of biochemical and biophysical events determined the course of life processes and attracted considerable interest and research. For example, modeling of biological networks and cellular responses relies on the availability of information on rate coefficients. Atomically detailed simulations hold the promise of supplementing experimental data to obtain a more complete kinetic picture. However, simulations at biological time scales are challenging. Typical computer resources are insufficient to provide the ensemble of trajectories at the correct length that is required for straightforward calculations of time scales. In the last years, new technologies emerged that make atomically detailed simulations of rate coefficients possible. Instead of computing complete trajectories from reactants to products, these approaches launch a large number of short trajectories at different positions. Since the trajectories are short, they are computed trivially in parallel on modern computer architecture. The starting and termination positions of the short trajectories are chosen, following statistical mechanics theory, to enhance efficiency. These trajectories are analyzed. The analysis produces accurate estimates of time scales as long as hours. The theory of Milestoning that exploits the use of short trajectories is discussed, and several applications are described.

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Section: The Use Of Short Trajectories To Simulate Long Time Kineticsmentioning

confidence: 99%

A new paradigm for atomically detailed simulations of kinetics in biophysical systems

Elber

2017

Quart. Rev. Biophys.

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112

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“…Extensive experimental and theoretical studies on RNA folding kinetics have provided significant insights into the kinetic mechanism of RNA functions (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). However, due to the complexity of the RNA folding energy landscape (37)(38)(39)(40)(41)(42)(43)(44)(45)(46) and the limitations of experimental tools (47)(48)(49)(50)(51)(52)(53)(54)(55), many fundamental problems, including single base flipping and base pair formation and fraying, remain unresolved. These unsolved fundamental problems have hampered our ability to resolve other important issues, such as RNA hairpin and larger structure folding kinetics.…”

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confidence: 99%

Understanding the kinetic mechanism of RNA single base pair formation

Chen

2015

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

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RNA functions are intrinsically tied to folding kinetics. The most elementary step in RNA folding is the closing and opening of a base pair. Understanding this elementary rate process is the basis for RNA folding kinetics studies. Previous studies mostly focused on the unfolding of base pairs. Here, based on a hybrid approach, we investigate the folding process at level of single base pairing/stacking. The study, which integrates molecular dynamics simulation, kinetic Monte Carlo simulation, and master equation methods, uncovers two alternative dominant pathways: Starting from the unfolded state, the nucleotide backbone first folds to the native conformation, followed by subsequent adjustment of the base conformation. During the base conformational rearrangement, the backbone either retains the native conformation or switches to nonnative conformations in order to lower the kinetic barrier for base rearrangement. The method enables quantification of kinetic partitioning among the different pathways. Moreover, the simulation reveals several intriguing ion binding/ dissociation signatures for the conformational changes. Our approach may be useful for developing a base pair opening/closing rate model. RNAs perform critical cellular functions at the level of gene expression and regulation (1-4). RNA functions are determined not only by RNA structure or structure motifs [e.g., tetraloop hairpins (5, 6)] but also by conformational distributions and dynamics and kinetics of conformational changes. For example, riboswitches can adopt different conformations in response to specific conditions of the cellular environment (7,8). Understanding the kinetics, such as the rate and pathways for the conformational changes, is critical for deciphering the mechanism of RNA function (9-19). Extensive experimental and theoretical studies on RNA folding kinetics have provided significant insights into the kinetic mechanism of RNA functions (19-36). However, due to the complexity of the RNA folding energy landscape (37-46) and the limitations of experimental tools (47-55), many fundamental problems, including single base flipping and base pair formation and fraying, remain unresolved. These unsolved fundamental problems have hampered our ability to resolve other important issues, such as RNA hairpin and larger structure folding kinetics. Several key questions remain unanswered, such as whether the hairpin folding is rate-limited by the conformational search of the native base pairs, whose formation leads to fast downhill folding of the whole structure, or by the breaking of misfolded base pairs before refolding to the native structure (18,19,(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73).Motivated by the need to understand the basic steps of nucleic acids folding, Hagan et al. (74) performed forty-three 200-ps unfolding trajectories at 400 K and identified both on-and offpathway intermediates and two dominant unfolding pathways for a terminal C-G base pair in a DNA duplex. In one of the pathways, bas...

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“…Notice that this class of energy functions generalizes the model for rough landscapes introduced by [58] and that similar potential energy functions have been used to model Wigner glasses [1]. We carry out Exact Milestoning in this example by solving boundary value problems, as described in [6]. The resulting stationary density obtained after convergence is shown in Figure 9.…”

Section: Rough Energy Landscapementioning

confidence: 95%