Metal ions and sugar puckering balance single-molecule kinetic heterogeneity in RNA and DNA tertiary contacts

Steffen, Fabio D; Khier, Mokrane; Kowerko, Danny; Cunha, Richard A.; Börner, Richard; Sigel, Roland K. O.

doi:10.1038/s41467-019-13683-4

Cited by 21 publications

(15 citation statements)

References 94 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Repuckering is not an unusual ribose transition, especially in the loop region of RNA structures. 72 Analyses performed using the CoSSMos database 73 revealed RNA structures having C4′-exo and C2′-exo puckers in the loop regions studied by NMR methods (Tables S5 and S6). If energetics would allow, it might be normal to observe C4′-exo and C2′-exo sugar puckers in RNA residues, but the balance between C4′-exo, C2′-exo, and C3′-endo is a missing piece in RNA force fields, which should be studied in detail in future work.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Evaluating Geometric Definitions of Stacking for RNA Dinucleoside Monophosphates Using Molecular Mechanics Calculations

Taghavi

Riveros

Wales

et al. 2022

J. Chem. Theory Comput.

View full text Add to dashboard Cite

RNA modulation via small molecules is a novel approach in pharmacotherapies, where the determination of the structural properties of RNA motifs is considered a promising way to develop drugs capable of targeting RNA structures to control diseases. However, due to the complexity and dynamic nature of RNA molecules, the determination of RNA structures using experimental approaches is not always feasible, and computational models employing force fields can provide important insight. The quality of the force field will determine how well the predictions are compared to experimental observables. Stacking in nucleic acids is one such structural property, originating mainly from London dispersion forces, which are quantum mechanical and are included in molecular mechanics force fields through nonbonded interactions. Geometric descriptions are utilized to decide if two residues are stacked and hence to calculate the stacking free energies for RNA dinucleoside monophosphates (DNMPs) through statistical mechanics for comparison with experimental thermodynamics data. Here, we benchmark four different stacking definitions using molecular dynamics (MD) trajectories for 16 RNA DNMPs produced by two different force fields (RNA-IL and ff99OL3) and show that our stacking definition better correlates with the experimental thermodynamics data. While predictions within an accuracy of 0.2 kcal/mol at 300 K were observed in RNA CC, CU, UC, AG, GA, and GG, stacked states of purine−pyrimidine and pyrimidine− purine DNMPs, respectively, were typically underpredicted and overpredicted. Additionally, population distributions of RNA UU DNMPs were poorly predicted by both force fields, implying a requirement for further force field revisions. We further discuss the differences predicted by each RNA force field. Finally, we show that discrete path sampling (DPS) calculations can provide valuable information and complement the MD simulations. We propose the use of experimental thermodynamics data for RNA DNMPs as benchmarks for testing RNA force fields.

show abstract

Section: ■ Results and Discussionmentioning

confidence: 99%

Evaluating Geometric Definitions of Stacking for RNA Dinucleoside Monophosphates Using Molecular Mechanics Calculations

Taghavi

Riveros

Wales

et al. 2022

J. Chem. Theory Comput.

View full text Add to dashboard Cite

show abstract

“…In nature, the most common helical topologies of DNA and RNA are the B‐form (C2'‐endo) and A‐form (C3'‐endo), respectively. The barrier for interconversion of these topologies in DNA duplex structures is small, as supported by several NMR and computational studies 88,92–94 …”

Section: Key Structural Studies Of Polymerasesmentioning

confidence: 89%

“…The barrier for interconversion of these topologies in DNA duplex structures is small, as supported by several NMR and computational studies. 88,[92][93][94] Despite the preferred C2'-endo conformation of the B-form of DNA duplexes, several crystallographic structures of A-, B-, X-, and Y-family DNA Pols show the 3 0 -end of the primer adopting a C3'-endo conformation either in pre-or postreactant state. 62,83,86,[95][96][97][98][99][100] The impact of the sugar pucker conformation on catalytic efficiency (k cat /K M ) was tested for both Pol β 101 and Pol η 86 using a primer with a ribonucleotide (C3'-endo) at the 3 0 end.…”

Section: Sugar Pucker Conformations During Catalysismentioning

confidence: 99%

Computational investigations of polymerase enzymes: Structure, function, inhibition, and biotechnology

Geronimo

Vidossich

Donati

et al. 2021

WIREs Comput Mol Sci

View full text Add to dashboard Cite

DNA and RNA polymerases (Pols) are central to life, health, and biotechnology because they allow the flow of genetic information in biological systems. Importantly, Pol function and (de)regulation are linked to human diseases, notably cancer (DNA Pols) and viral infections (RNA Pols) such as COVID‐19. In addition, Pols are used in various applications such as synthesis of artificial genetic polymers and DNA amplification in molecular biology, medicine, and forensic analysis. Because of all of this, the field of Pols is an intense research area, in which computational studies contribute to elucidating experimentally inaccessible atomistic details of Pol function. In detail, Pols catalyze the replication, transcription, and repair of nucleic acids through the addition, via a nucleotidyl transfer reaction, of a nucleotide to the 3′‐end of the growing nucleic acid strand. Here, we analyze how computational methods, including force‐field‐based molecular dynamics, quantum mechanics/molecular mechanics, and free energy simulations, have advanced our understanding of Pols. We examine the complex interaction of chemical and physical events during Pol catalysis, like metal‐aided enzymatic reactions for nucleotide addition and large conformational rearrangements for substrate selection and binding. We also discuss the role of computational approaches in understanding the origin of Pol fidelity—the ability of Pols to incorporate the correct nucleotide that forms a Watson–Crick base pair with the base of the template nucleic acid strand. Finally, we explore how computations can accelerate the discovery of Pol‐targeting drugs and engineering of artificial Pols for synthetic and biotechnological applications. This article is categorized under: Structure and Mechanism > Reaction Mechanisms and Catalysis Structure and Mechanism > Computational Biochemistry and Biophysics Software > Molecular Modeling

show abstract

“…In basic research, fluorescently labeled nucleic acids are widely used in bulk and single-molecule experiments to elucidate fundamental processes, such as folding, 2 replication, transcription and translation. [3][4][5][6] In cells, fluorescent labeling is needed to visualize the subcellular localization of nucleic acids, most importantly mRNAs.…”

Section: Introductionmentioning

confidence: 99%

Covalent labeling of nucleic acids

2020

View full text Add to dashboard Cite

show abstract

Metal ions and sugar puckering balance single-molecule kinetic heterogeneity in RNA and DNA tertiary contacts

Cited by 21 publications

References 94 publications

Evaluating Geometric Definitions of Stacking for RNA Dinucleoside Monophosphates Using Molecular Mechanics Calculations

Evaluating Geometric Definitions of Stacking for RNA Dinucleoside Monophosphates Using Molecular Mechanics Calculations

Computational investigations of polymerase enzymes: Structure, function, inhibition, and biotechnology

Covalent labeling of nucleic acids

Contact Info

Product

Resources

About