Threocytidines: Insight into the Conformational Preferences of Artificial Threose Nucleic Acid (TNA) Building Blocks in B3LYP Studies

Bednarko, Justyna; Stachurski, Oktawian; Wielińska, Justyna; Kozakiewicz, Karol; Liberek, Beata; Nowacki, Andrzej

doi:10.1016/j.jmgm.2018.01.007

Cited by 3 publications

(2 citation statements)

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“…[1][2][3][4][5][6][7][8] One of the simplest analogues of DNA is threofuranosyl nucleic acid (TNA), in which the internucleotide linkages are shifted from the wild-type 5'-to-3' direction to 3'-to-2' one. 9,10 The generated TNA has been shown to have the following benefits: (1) It is able to form stable duplexes with DNA, RNA, and TNA, 4,7,[11][12][13][14][15][16] which enables it to transfer information to DNA or RNA. (2) The enzymatic and nonenzymatic polymerization of the TNA nucleotide is possible due to this cross-pairing with other polynucleotides.…”

Section: Introductionmentioning

confidence: 99%

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

Sun

Zhang

2021

CCS Chem

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Section: Introductionmentioning

confidence: 99%

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

Sun

Zhang

2021

CCS Chem

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“…[1][2][3][4][5][6][7][8] One of the simplest analogues of DNA is threofuranosyl nucleic acid (TNA), the inter-nucleotide linkages of which are shifted from the wild-type 5'to-3' one to the 3'-to-2' one. [9][10] TNA is able to form stable duplexes with DNA, RNA and TNA, 4,7,[11][12][13][14][15][16] which enables it to transfer information to DNA or RNA. The enzymatic and non-enzymatic polymerization of the TNA nucleotide is also made possible due to this cross-pairing.…”

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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Conformational preferences of guanine-containing threose nucleic acid building blocks in B3LYP studies

Konieczna,

Wrońska,

Kalińska

et al. 2024

Carbohydrate Research

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Threocytidines: Insight into the Conformational Preferences of Artificial Threose Nucleic Acid (TNA) Building Blocks in B3LYP Studies

Cited by 3 publications

References 61 publications

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

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

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

Conformational preferences of guanine-containing threose nucleic acid building blocks in B3LYP studies

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