Additive <scp>CHARMM</scp> force field for naturally occurring modified ribonucleotides

Xu, You; Vanommeslaeghe, Kenno; Aleksandrov, Alexey; MacKerell, Alexander D.; Nilsson, Lennart

doi:10.1002/jcc.24307

Cited by 74 publications

(95 citation statements)

References 122 publications

(215 reference statements)

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“…[32] The four tRNAs have the same sequence length in ASL, TSL and AS. The only length difference is in the DSL where 1EHZ and 1FIR have the standard 8 nucleotides in the loop, whereas 1YFG and 3CW5 have 7 and 9 nucleotides, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…The CHARMM36 force field for nucleic acids,[36,37] including the recent extension for modified nucleotides[32] and the CHARMM General Force Field[38,39] were used.…”

Section: Methodsmentioning

confidence: 99%

“…The ribose pucker was defined by the pseudorotation phase angle P ,[44] and in this paper it was simply denoted as north (−90° < P ≤ 90°) and south ( 90° < P ≤ 270°). The criteria of base stacking are similar as previously published[32]: 1) the distance between two glycosidic nitrogen atoms R ≤ 5 Å; 2) the pseudo dihedral formed by two base-axis atoms, i.e. N1-C4 of Y or N9-C6 of R, ( Φ 0 – 40°) ≤ Φ ≤ ( Φ 0 + 40°); and 3) the angle between normal vectors of the two bases, Θ ≤ 40° or Θ ≥ 140°, where Φ 0 is the value when two bases are stacking in the ideal A-RNA geometry ( Φ 0 ≈ 20° for 5′-R-R-3′ or 5′-Y-Y-3′, Φ 0 ≈ 40° for 5′-R-Y-3′ and Φ 0 ≈ 0° for 5′-Y-R-3′ context).…”

Section: Methodsmentioning

confidence: 99%

“…[28,29,30,31] In the present manuscript we report MD simulations of select tRNAs using the CHARMM36 force field[32] that was recently extended to included modified nucleotides. The simulations are designed to investigate the influence of the nucleotide modifications on tRNA structure and dynamics as well as the impact of Mg 2+ .…”

Section: Introductionmentioning

confidence: 99%

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Structural effects of modified ribonucleotides and magnesium in transfer RNAs

MacKerell

Nilsson

2016

Bioorganic & Medicinal Chemistry

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Modified nucleotides are ubiquitous and important to tRNA structure and function. To understand their effect on tRNA conformation, we performed a series of molecular dynamics simulations on yeast tRNAPhe and tRNAinit, E. coli tRNAinit and HIV tRNALys. Simulations were performed with the wild type modified nucleotides, using the recently developed CHARMM compatible force field parameter set for modified nucleotides [Xu, Y., Vanommeslaeghe, K., Aleksandrov, A., Mackerell AD, Nilsson, L., J. Comp. Chem., 2016], or with the corresponding unmodified nucleotides, and in the presence or absence of Mg2+. Results showed a stabilizing effect associated with the presence of the modifications and Mg2+ for some important positions, such as modified guanosine in position 37 and dihydrouridines in 16/17 including both structural properties and base interactions. Some other modifications were also found to make subtle contributions to the structural properties of local domains. While we were not able to investigate the effect of Adenosine 37 in tRNAinit and limitations were observed in the conformation of E. coli tRNAinit, the presence of the modified nucleotides and of Mg2+ better maintained the structural features and base interactions of the tRNA systems than in their absence indicating the utility of incorporating the modified nucleotides in simulations of tRNA and other RNAs.

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Section: Resultsmentioning

confidence: 99%

“…The CHARMM36 force field for nucleic acids,[36,37] including the recent extension for modified nucleotides[32] and the CHARMM General Force Field[38,39] were used.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structural effects of modified ribonucleotides and magnesium in transfer RNAs

MacKerell

Nilsson

2016

Bioorganic & Medicinal Chemistry

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“…39,42 Once a productive complex has been reached, the nucleobase cleavage rate would depend inversely on the strength of the glycosyl bond, which is lower in f C and ca C than for cytosine itself. 43 We note that f C has a conformationally restrained formyl group 44 and a large dipole moment with different directionality from that of C. 45 It has the potential to form strong polar interactions at the TDG enzyme recognition site. It also has high N1 acidity and a weaker N1-C1′ bond, so under appropriate conditions it is a good leaving group.…”

Section: Discussionmentioning

confidence: 97%

5-Formylcytosine does not change the global structure of DNA

Hardwick

Ptchelkine

El‐Sagheer

et al. 2017

Nat Struct Mol Biol

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The mechanism by which 5-formylcytosine (fC) is recognised by enzymes involved in epigenetic modification and reading of DNA is not known, and recently an unusual DNA structure (F-DNA) was proposed as the basis for enzyme recognition of clusters of fC. We used NMR and X-ray crystallography to compare several modified DNA duplexes with the unmodified analogues and show that in the crystal state they all belong to the A-family, but in solution they are all members of the B-family. Contrary to the previous study, we find that 5-formylcytosine does not significantly affect the structure of DNA, though there are modest local differences at the modification sites. Hence, global conformation changes are unlikely to account for the recognition of this modified base, and our structural data favour a mechanism that operates at base-pair resolution for the recognition of 5-formylcytosine by epigenome-modifying enzymes.

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Suppression of Lung Cancer Malignancy by Micellized siRNA through Cell Cycle Arrest

Kim

Jeong

Choi

et al. 2023

Adv Healthcare Materials

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UBA6-specific E2 conjugation enzyme 1 (USE1) is frequently overexpressed in lung cancer patients. Moreover, the critical role of USE1 in the progression of human lung cancer is also indicated. As the next step, the authors aim to develop USE1-targeted therapeutic agents based on RNA interference (RNAi). In this study, a lipid-modified DNA carrier, namely U4T, which consists of four consecutive dodec-1-ynyluracil (U) nucleobases to increase the cell permeability of siRNA targeting of USE1 is introduced. The U4Ts aggregate to form micelles, and the USE1-silencing siRNA-incorporated soft spherical nucleic acid aggregate (siSNA) can be created simply through base-pairing with siRNA. Treatment with siSNA is effective in suppressing tumor growth in vivo as well as cell proliferation, migration, and invasion of lung cancer cells. Furthermore, siSNA inhibited tumor cell growth by inducing cell cycle arrest in the G1 phase and apoptosis. Thus, the anti-tumor efficacy of siSNA in lung cancer cell lines and that siSNA possesses effective cell-penetrating ability without using cationic transfection moieties are confirmed. Collectively, these results suggest that siSNA can be applied to the clinical application of RNAi-based therapeutics for lung cancer treatment.

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Additive CHARMM force field for naturally occurring modified ribonucleotides

Cited by 74 publications

References 122 publications

Structural effects of modified ribonucleotides and magnesium in transfer RNAs

Structural effects of modified ribonucleotides and magnesium in transfer RNAs

5-Formylcytosine does not change the global structure of DNA

Suppression of Lung Cancer Malignancy by Micellized siRNA through Cell Cycle Arrest

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