Reaction Coordinate and Thermodynamics of Base Flipping in RNA

Levintov, Lev; Paul, Sanjib; Vashisth, Harish

doi:10.1021/acs.jctc.0c01199

Cited by 10 publications

(10 citation statements)

References 67 publications

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“…In addition, we observed that nucleotide U7 flips inward and points toward the core of the HIV-1 Tar RNA in both the bound B1 and B2 low-energy conformations (Figure 5B,C) and the 1UUD 67 PDB structure, while it flips outward in the unbound U low-energy conformation (Figure 5G). The observation of the nucleotide U7 "base-flipping" 77 phenomenon during ligand binding illustrated the importance of this nucleotide in the ligand binding to the HIV-1 Tar RNA. Furthermore, two slightly different binding pathways of the rbt203 ligand to the HIV-1 Tar RNA could be observed from the free energy profile in Figure 5.…”

Section: ■ Discussionmentioning

confidence: 99%

Gaussian Accelerated Molecular Dynamics in OpenMM

et al. 2022

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Gaussian accelerated molecular dynamics (GaMD) is a computational technique that provides both unconstrained enhanced sampling and free energy calculations of biomolecules. Here, we present the implementation of GaMD in the OpenMM simulation package and validate it on model systems of alanine dipeptide and RNA folding. For alanine dipeptide, 30 ns GaMD production simulations reproduced free energy profiles of 1000 ns conventional molecular dynamics (cMD) simulations. In addition, GaMD simulations captured the folding pathways of three hyperstable RNA tetraloops (UUCG, GCAA, and CUUG) and binding of the rbt203 ligand to the HIV-1 Tar RNA, both of which involved critical electrostatic interactions such as hydrogen bonding and base stacking. Together with previous implementations, GaMD in OpenMM will allow for wider applications in simulations of proteins, RNA, and other biomolecules.

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Section: ■ Discussionmentioning

confidence: 99%

Gaussian Accelerated Molecular Dynamics in OpenMM

et al. 2022

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“…If the stable states A and B are separated by a high free energy barrier, an enhanced sampling scheme is often necessary to explore the low probability, rare configurations at the kinetic bottlenecks of the associated transition. , Many studies on enzyme catalyzed chemical reactions employ one or more bias potentials along a set of collective variables (CVs) such as interatomic distances, angles, and dihedral angles that may be chosen empirically or by automated machine learning methods. ,− An unbiased enhancement in sampling, on the other hand, may be achieved through methods such as transition path sampling (TPS), ,,− transition interface sampling (TIS), − and their latest variants . These methods involve a Markov chain Monte Carlo in the trajectory space, thereby circumventing the problem of knowing the CVs to be sampled a priori .…”

Section: Introductionmentioning

confidence: 99%

Nonlinear Reaction Coordinate of an Enzyme Catalyzed Proton Transfer Reaction

Paul

Taraphder

2022

J. Phys. Chem. B

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We present an in-depth study on the theoretical calculation of an optimum reaction coordinate as a linear or nonlinear combination of important collective variables (CVs) sampled from an ensemble of reactive transition paths for an intramolecular proton transfer reaction catalyzed by the enzyme human carbonic anhydrase (HCA) II. The linear models are optimized by likelihood maximization for a given number of CVs. The nonlinear models are based on an artificial neural network with the same number of CVs and optimized by minimizing the root-mean-square error in comparison to a training set of committor estimators generated for the given transition. The nonlinear reaction coordinate thus obtained yields the free energy of activation and rate constant as 9.46 kcal mol–1 and 1.25 × 106 s–1, respectively. These estimates are found to be in quantitative agreement with the known experimental results. We have also used an extended autoencoder model to show that a similar analysis can be carried out using a single CV only. The resultant free energies and kinetics of the reaction slightly overestimate the experimental data. The implications of these results are discussed using a detailed microkinetic scheme of the proton transfer reaction catalyzed by HCA II.

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“…Previous literature results have also shown the benefits of incorporating watercoordination-based CVs for obtaining PMFs for the translocation of charged or polar molecules across a lipid bilayer. 43,44 These results indicate that future work should consider the further refinement of current CVs 56,57 and alternative CVs that capture variations in local water density to augment geometric CVs when considering the translocation or flipping of complex molecules such as the peptides studied here.…”

Section: ■ Results and Discussionmentioning

confidence: 85%

Analysis of Charged Peptide Loop-Flipping across a Lipid Bilayer Using the String Method with Swarms of Trajectories

Patel

Lehn

2021

J. Phys. Chem. B

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The hydrophobic core of the lipid bilayer is conventionally considered a barrier to the translocation of charged species such that the translocation of even single ions occurs on long time scales. In contrast, experiments have revealed that some materials, including peptides, proteins, and nanoparticles, can translocate multiple charged moieties across the bilayer on experimentally relevant time scales. Understanding the molecular mechanisms underlying this behavior is challenging because resolving corresponding free-energy landscapes with molecular simulation techniques is computationally expensive. To address this challenge, we use atomistic molecular dynamics simulations with the swarms-of-trajectories (SOT) string method to analyze charge translocation pathways across single-component lipid bilayers as a function of multiple collective variables. We first demonstrate that the SOT string method can reproduce the free-energy barrier for the translocation of a charged lysine amino acid analogue in good agreement with the literature. We then obtain minimum free-energy pathways for the translocation, or flipping, of charged peptide loops across the lipid bilayer by utilizing trajectories from prior temperature-accelerated molecular dynamics (TAMD) simulations as initial configurations. The corresponding potential of mean force calculations reveal that the protonation of a central membrane-exposed aspartate residue substantially reduces the free-energy barrier for flipping charged loops by modulating the water content of the bilayer. These results provide new insight into the thermodynamics underlying loop-flipping processes and highlight how the combination of TAMD and the SOT string method can be used to understand complex charge translocation mechanisms.

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Reaction Coordinate and Thermodynamics of Base Flipping in RNA

Cited by 10 publications

References 67 publications

Gaussian Accelerated Molecular Dynamics in OpenMM

Gaussian Accelerated Molecular Dynamics in OpenMM

Nonlinear Reaction Coordinate of an Enzyme Catalyzed Proton Transfer Reaction

Analysis of Charged Peptide Loop-Flipping across a Lipid Bilayer Using the String Method with Swarms of Trajectories

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