Parametrization of 2-thiouracil and 4-thiouracil in CHARMM all-atom empirical force field

Sarzyñska, Joanna; Kuliński, Tadeusz

doi:10.12921/cmst.2005.11.01.49-55

Cited by 7 publications

(4 citation statements)

References 30 publications

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“…MD simulations were performed using the program NAMD 2.9 ( 32 ) with the CHARM27 parameter set modified to include parameters for s 2 U ( 33 ). All simulations used periodic boundary conditions with Langevin dynamics and a Langevin piston ( 34 ) to maintain the temperature at 298.15 K (with a damping constant of 5 ps −1 ) and the pressure at 1 atm.…”

Section: Methodsmentioning

confidence: 99%

Thermodynamic insights into 2-thiouridine-enhanced RNA hybridization

et al. 2015

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Nucleobase modifications dramatically alter nucleic acid structure and thermodynamics. 2-thiouridine (s2U) is a modified nucleobase found in tRNAs and known to stabilize U:A base pairs and destabilize U:G wobble pairs. The recently reported crystal structures of s2U-containing RNA duplexes do not entirely explain the mechanisms responsible for the stabilizing effect of s2U or whether this effect is entropic or enthalpic in origin. We present here thermodynamic evaluations of duplex formation using ITC and UV thermal denaturation with RNA duplexes containing internal s2U:A and s2U:U pairs and their native counterparts. These results indicate that s2U stabilizes both duplexes. The stabilizing effect is entropic in origin and likely results from the s2U-induced preorganization of the single-stranded RNA prior to hybridization. The same preorganizing effect is likely responsible for structurally resolving the s2U:U pair-containing duplex into a single conformation with a well-defined H-bond geometry. We also evaluate the effect of s2U on single strand conformation using UV- and CD-monitored thermal denaturation and on nucleoside conformation using 1H NMR spectroscopy, MD and umbrella sampling. These results provide insights into the effects that nucleobase modification has on RNA structure and thermodynamics and inform efforts toward improving both ribozyme-catalyzed and nonenzymatic RNA copying.

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Section: Methodsmentioning

confidence: 99%

Thermodynamic insights into 2-thiouridine-enhanced RNA hybridization

et al. 2015

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“…Until recently, the systematic development and validation of the force field parameters for modified RNAs were neglected [5,[46][47][48][49][50][51][52][53][54][55] (http://www.pharmacy.manchester.ac.uk/ bryce/amber). Aduri et al [56] first attempted the systematic development of AMBER force field parameter sets for 107 naturally occurring RNA modifications.…”

Section: Introductionmentioning

confidence: 99%

Reparameterizations of theχTorsion and Lennard-JonesσParameters Improve the Conformational Characteristics of Modified Uridines

et al. 2016

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2014, 54, 1129-1142). Here, we report an approach for the development and fine tuning of the AMBER force field parameters for 2-thiouridine, 4-thiouridine, and pseudouridine with diverse conformational preferences. The χ torsion parameters were reparameterized at the individual nucleoside level. The effect of combining the revised γ torsion parameter and modifying the Lennard-Jones σ parameters were also tested by directly comparing the conformational preferences obtained from our extensive molecular dynamics simulations with those from experimental observations. © 2016 Wiley Periodicals, Inc.

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“…The poor performance of the MM FC model might not be caused by the FC approximation per se (which is adequate for the neutral G and A ) but rather by the insufficiency of the charge parametrization procedure (based on protocols of refs and ) in the case of the DC. For example, the largest difference in the atomic partial charges between the neutral G and G •+ in the MM simulations occurs for atoms N9 (−0.15), H8 (+0.16), N3 (+0.19), O6 (+0.21), and C8 (+0.33).…”

Section: Resultsmentioning

confidence: 99%

“…To the best of our knowledge, no MM simulations of G or A DCs were performed previously; therefore, no parameters existed for the DCs in CHARMM. We constructed the atomic partial charges for the DC following the standard CHARMM protocol of MacKerell et al , First, charge density differences between the neutral base and DC atoms were determined by QM (DFT/B3LYP/aug-cc-pVDZ level of theory in Gaussian03). The differences were added to the CHARMM atomic charges of the neutral base, resulting in the initial guess for the DC charges.…”

Section: Methodsmentioning

confidence: 99%

Is MD Geometry Sampling Sufficient for Nucleobase Electronic Structure Analysis of ET Reactions? Comparing Classical MD and QM/MM Methods

et al. 2010

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It has been shown in many experimental studies that one of the major charge-transfer mechanisms in nucleic acids is that by positive charge carriers (holes), residing predominantly on G bases. Theoretical charge-transfer calculations often use Koopmans’ theorem to approximate the relaxed doublet cation hole energies from simulations of the neutral ground state (GS). An assumption in these calculations is that the geometry and interactions of the doublet cation (DC) hole with the solvent is the same as that for the neutral GS. Here, we simulate the DC hole on solvated G and A nucleobases using combined quantum mechanics/molecular mechanics (QM/MM) methods and compare the geometries and electronic structure of the charged bases to those of the neutral bases. We also study the effects of the solvent environment on the nucleobase electronic structure and estimate the size of the smallest solvent shell that needs to be included in order to achieve convergence of the nucleobase energy levels. We find that Koopmans’ theorem based methods provide a satisfactory description of the nucleobase energy levels, with the largest deviation (∼0.1eV) for charged bases in explicit water. We also find that the size of the solvent shell is crucial for describing the nucleobase electronic structure. When the solvent is properly accounted for, we find that the average energy separation between the hole energy levels on isolated G and A is ∼0.2 eV, and the hole energy levels fluctuate by ∼0.3 eV. These findings suggest important corrections to earlier theoretical studies that overestimated the hole energy separation among nucleobases and underestimated or neglected the base energy distribution due to thermal fluctuations of the nucleobases and their environment. Our results further suggest that hopping charge transport plays an important role even at short distances.

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Parametrization of 2-thiouracil and 4-thiouracil in CHARMM all-atom empirical force field

Cited by 7 publications

References 30 publications

Thermodynamic insights into 2-thiouridine-enhanced RNA hybridization

Thermodynamic insights into 2-thiouridine-enhanced RNA hybridization

Reparameterizations of theχTorsion and Lennard-JonesσParameters Improve the Conformational Characteristics of Modified Uridines

Is MD Geometry Sampling Sufficient for Nucleobase Electronic Structure Analysis of ET Reactions? Comparing Classical MD and QM/MM Methods

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