An Atomistic View of DNA Dynamics and Its Interaction with Small Binders: Insights from Molecular Dynamics and Principal Component Analysis

Fresch, Barbara; Remacle, Françoise

doi:10.1007/978-3-319-13872-5_2

Cited by 2 publications

(2 citation statements)

References 39 publications

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“…Previous pulling simulations suggested that a 3′-base is more stable than its 5′-base pairing partner. In a folding reaction, the 3′-base is likely to fold first through single-stranded base stacking, followed by folding of the 5′-base through base pairing with the 3′-base (75,84,95,96). Here, we focus on the second step, namely, the folding kinetics of the 5′-base (nucleotide G1) after the 3′-base (nucleotide C6) is folded into the native state (Fig.…”

Section: Methodsmentioning

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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Section: Methodsmentioning

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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“…S8, ESI) were refined with an all-atom molecular mechanics simulation (AMBER Score) where the whole protein is flexible and the binding site can adjust its structure to the specific ligand. [26][27][28] The values of the scoring functions are reported in Table S5 (ESI), negative values indicate favorable binding. The affinities evaluated by rigid docking of PK11195 and TZ6 for the target protein are comparable, while the interaction of 1 with the rigid binding pocket is repulsive because of the increased van der Waals radius due to the presence of the CuBr2 moiety.…”

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confidence: 99%