Thermodynamic Insights of Base Flipping in TNA Duplex: Force Fields, Salt Concentrations, and Free-Energy Simulation Methods

Sun, Zhaoxi; Zhang, John Z.H.

doi:10.31635/ccschem.020.202000202

Cited by 25 publications

(22 citation statements)

References 150 publications

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“…Gaussian height, the deposition interval of 0.5 ps, the bias factor of 20, and the Gaussian widths of 0.1 nm, 16  , and 8  for the three polar coordinates, respectively. The simulation is performed with GROMACS 2019.6 104 patched with PLUMED 2.7.0 105 .…”

Section: Free Energy Simulationsmentioning

confidence: 99%

“…Biologically relevant processes generally happen at time scales of μs, ms and even longer, which are inaccessible in modern computational modelling. [8][9][10][11][12][13][14][15][16] Enhanced sampling techniques are often employed to deal with the time-scale problem. [17][18][19][20][21][22][23] Modifications of the Hamiltonian of the simulated system are added to accelerate the phase space exploration, and post-simulation analyses are used to recover the statistics in the original unperturbed ensemble.…”

Section: Introductionmentioning

confidence: 99%

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A General Picture of Cucurbit[8]uril Host-Guest Binding

Sun

Huai

et al. 2021

Preprint

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Describing, understanding, and designing complex interaction networks within macromolecular systems remain challenging in modern chemical research. Host-guest systems, despite their relative simplicity in both the structural feature and interaction patterns, still pose problems in theoretical modelling. The barrelshaped supra-molecular container Cucurbit[8]uril (CB8) shows promising functionalities in various areas, e.g., catalysis and molecular recognition. It can stably coordinate a series of structurally diverse guests with high affinities. In this work, we examine the binding of 7 commonly abused drugs to the CB8 host, aiming at providing a general picture of CB8-guest binding. A thorough comparison of widely used fixed-charge models for drug-like molecules is presented. Extensive sampling of the configurational space of these hostguest systems is performed, and the binding pathway and interaction patterns of CB8-guest complexes are investigated in detail. Iterative refitting of the atomic charges suggests significant conformation-dependence of charge generation. The initial model generated at the original conformation could be inaccurate for new conformations explored during conformational search. Our investigations of the configurational space of CB8-drug complexes suggest that the host-guest interactions are more complex than expected. Despite the structural simplicities of these molecules, the conformational fluctuations of the host and the guest molecules and orientations of functional groups lead to the existence of an ensemble of binding modes (e.g., bracelet-like guest conformations and crescent free energy landscapes). Thus, understandings obtained from static calculations based on a single or several structures are limited for these host-guest interactions. The 2 / 80 investigation protocol provides useful guidelines for studying host-guest binding, and the insights of the binding thermodynamics, performance of fixed-charge models, and binding patterns of the CB8-guest systems are useful for elucidating the binding mechanism of other host-guest complexes.

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Section: Free Energy Simulationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A General Picture of Cucurbit[8]uril Host-Guest Binding

Sun

Huai

et al. 2021

Preprint

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“…The seventh base residue is at the center of the duplex, and thus, its flipping is likely influenced at a minimal level by the terminal fraying effect, which led us to study the flipping of this base residue. We used the high-quality atomic charge scheme, AM1-BCC, 84,85 a reliable amber force field program, AMBER14SB, 86 and the general AMBER force field (GAFF) 87 in comparative MD simulations study of DNA and TNA to parameterize the mutated T residue, which is named as TFT in our current work. We studied the flipping of the seventh residue of the canonical T mutation to TFT by investigating the variations in thermodynamics of the DNA<->TNA mutation.…”

Section: Preparation Of the Reaction Systemmentioning

confidence: 99%

“…Such a huge gap between the timescale accessible in MD simulations and that of base flipping makes it hard to acquire converged statistics in computer simulations. Thus, to obtain converged and statistically meaningful data, equilibrium-enhanced sampling techniques such as umbrella sampling [44][45][46][47][48] and replica-exchange methods [49][50][51][52][53][54][55] are often employed. For instance, an umbrella sampling is applied to study the protonation-dependent behavior of base flipping (P-DBBF) in RNA systems, the P-DBBF was found to couple with a syn-to-anti transformation of a guanine (G) group in the G-adenine (A) mismatch.…”

Section: Introductionmentioning

confidence: 99%

Thermodynamic Insights of Base Flipping in TNA Duplex: Force Fields, Salt Concentrations, and Free Energy Simulation Methods

Sun¹,

Zhang²

2020

Preprint

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<p>Threofuranosyl nucleic acid (TNA) is an analogue of DNA. Its inter-nucleotide linkages are shifted from the wild-type 5'-to-3' one to the 3'-to-2' one. As a result, the number of covalent bonds between consecutive phosphates is reduced from 6 to 5. This leads to higher chemical stability, less reactive groups, and lower conformational flexibility. Experimental observations indicate that the interaction network is perturbed at the minimal level and the thermodynamic stability of the duplex is unaltered upon the TNA mutation. Whether computational modelling could reproduce this result will be studied in the base flipping of the middle T (DNA) residue or its T-to-TFT mutation (TNA). We applied the equilibrium free energy simulation and the nonequilibrium stratification method proposed previously in the base flipping case, proving the applicability of alternative free energy simulation protocols. As the force field is the main accuracy-limiting factor when converged phase space sampling is obtained, we benchmarked three popular AMBER force fields for nucleotides. The last-generation force fields include bsc1 and OL15, both of which perform similarly in reproducing the structures near the crystal conformation in previous benchmark studies. Our results indicate that all these three force fields provide similar descriptions of the base-paired state. However, with free energy simulation constructing the free energy profiles along the conformational change pathway, high-energy regions are explored and these three force fields behave differently. The bsc1 force field is found to perform best in reproducing the similarity of stabilities of DNA and TNA duplexes. The free energy barrier of base flipping under the OL15 force field is lowered modestly in TNA, and thus this force field is also usable. However, the bsc0 force field provides wrong results. The TNA duplex is significantly less stable than the DNA duplex. Therefore, the bsc0 force field is not recommended in any application in modern nucleotide simulations. The salt concentration in nucleotide simulations is another factor influencing the thermodynamics of the system. Previous reports conclude that the net-neutral and excess-salt simulations provide similar results. However, the simulation method limits the phase space region explored in previous computational modelling. Our free energy simulation explores high-energy regions, where the excess salt does affect the thermodynamic stability. The free energy barrier along the base flipping pathway is generally elevated upon the addition of excess salts, but the relative height of the free energy barriers in DNA and TNA duplexes is not significantly changed. This phenomenon emphasizes the importance of adding sufficient salts to reproduce the experimental condition. </p>

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“…To obtain a reliable estimate of the free energy profile along the base flipping pathway, a series of intermediate states need to be introduced. [25][26][27] The more general forms of FEP and BAR are their nonequilibrium extensions, that is, Jarzynski's identity (JI) [28] and Crooks' equation (CE). [29] They generalize the energy difference in FEP and BAR to the microscopic nonequilibrium work (NEW) performed on the system.…”

Section: Introductionmentioning

confidence: 99%

BAR‐Based Multi‐Dimensional Nonequilibrium Pulling for Indirect Construction of QM/MM Free Energy Landscapes: Varying the QM Region

Sun

Liu

2021

Advcd Theory and Sims

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The indirect free energy simulation at quantum mechanics (QM)/ molecular mechanics (MM) levels provides a feasible alternative to direct QM/MM simulations. The main idea under the indirect method is constructing a thermodynamic cycle, exploring the configurational space under a cheaper but less accurate QM level, and performing an alchemical correction to obtain the thermodynamics under an accurate but computationally demanding QM level. In the authors' previous works, a multi-dimensional nonequilibrium free energy simulation framework was developed to obtain QM/MM free energy landscapes indirectly, where the QM theory is varied but the other details of the multi-scale treatment remain unchanged. In this work, the possibility of changing the region for electronic structure calculations in the multi-scale treatment is explored. Numerical tests are performed for the conformational change in a biologically relevant peptide in vacuo and in solution, and the QM region and QM level are varied simultaneously. Unidirectional and bidirectional equilibrium perturbations are also performed for comparison. The indirect estimates from the nonequilibrium perturbation framework are almost identical to the direct results, while the indirect equilibrium estimates show obvious deviations from the direct references. They further derive the acceleration ratio of the indirect scheme to understand when the indirect scheme prevails.

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Thermodynamic Insights of Base Flipping in TNA Duplex: Force Fields, Salt Concentrations, and Free-Energy Simulation Methods

Abstract: Citation denotes calendar and volume year of first online publication.

Cited by 25 publications

References 150 publications

A General Picture of Cucurbit[8]uril Host-Guest Binding

A General Picture of Cucurbit[8]uril Host-Guest Binding

Thermodynamic Insights of Base Flipping in TNA Duplex: Force Fields, Salt Concentrations, and Free Energy Simulation Methods

BAR‐Based Multi‐Dimensional Nonequilibrium Pulling for Indirect Construction of QM/MM Free Energy Landscapes: Varying the QM Region

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