Determinants of the Unexpected Stability of RNA Fluorobenzene Self Pairs

Kopitz, Hannes; Živković, Aleksandra; Engels, Joachim W.; Gohlke, Holger

doi:10.1002/cbic.200800461

Cited by 39 publications

(39 citation statements)

References 53 publications

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“…The actual interplay of all these forces is presently entirely unknown and deserves further studies, theoretical as well as experimental. 127 Note that the balance of forces may be very different in different types of nucleic acids and even different in different steps of the same nucleic acid form, and may require to be studied literally case by case.…”

mentioning

confidence: 99%

Comparison of Intrinsic Stacking Energies of Ten Unique Dinucleotide Steps in A-RNA and B-DNA Duplexes. Can We Determine Correct Order of Stability by Quantum-Chemical Calculations?

Svozil¹,

Hobza²,

Šponer³

2010

J. Phys. Chem. B

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High level ab initio methods have been used to study stacking interactions in ten unique base pair steps both in A-RNA and in B-DNA duplexes. The protocol for selection of geometries based on molecular dynamics (MD) simulations is proposed, and its suitability is demonstrated by comparison with stacking in steps at fiber diffraction geometries. It is shown that fiber diffraction geometries are not sufficiently accurate for interaction energy calculations. In addition, the protocol for selection of geometries based on MD simulations allows for the evaluation of the variability of the intrinsic stacking energies along the MD trajectories. The uncertainty in stacking energies (difference between the most and least stable geometry) due to the dynamical nature of systems can be, in some cases, as large as 3.0 kcal · mol, which is almost 50% of the actual sequence dependence of base stacking energies (the energy difference between the most and least stable sequences). Thus, assessing the relative magnitude of the gas phase stacking energy using a single geometry for each sequence is insufficient to obtain an unambiguous order of gas phase stacking energies in canonical double helices. Though the ordering of ten unique dinucleotide steps cannot be definitive, some general conclusions were drawn. The stacking energies of base pair steps in A-RNA are more evenly separated compared to B-DNA, and their ordering is less sensitive to the dynamics of the system compared to be B-DNA. The most stable step both in B-DNA and A-RNA is the CG/CG step that is well separated from the second most stable step GC/GC. Also the least stable step (the CC/GG step) is well separated from the rest of the structures. The calculations further show that B-DNA stacking is favorable only marginally (on average by 1.14 kcal · mol -1 per base pair step) over A-RNA stacking, and this difference vanishes after subtracting the stabilizing van der Waals effect of the thymine 5-methyl group that is absent in RNA. Basically, no correlation between the sequence dependence of gas phase stacking energies and the sequence dependence of ∆G°3 7 free energies used in nearest-neighbor models was found either for B-DNA or for A-RNA. This reflects the complexity of the balance of forces that are responsible for the sequence dependence of thermodynamics stability of nucleic acids, which masks the effect of the intrinsic interactions between the stacked base pairs.

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mentioning

confidence: 99%

Comparison of Intrinsic Stacking Energies of Ten Unique Dinucleotide Steps in A-RNA and B-DNA Duplexes. Can We Determine Correct Order of Stability by Quantum-Chemical Calculations?

Svozil¹,

Hobza²,

Šponer³

2010

J. Phys. Chem. B

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“…A good balance of intermolecular forces is most crucial when it comes to determining relative free energies of stability of RNA duplexes that differ only marginally with respect to the base composition. Reassuringly, when investigating the determinants of the unexpected stability of RNA fluorobenzene self pairs by means of thermodynamic integration calculations using the parm94 force field , we were able to reproduce experimental relative free energies of stability to < 0.4 kcal mol À1 deviation, with a correlation between experimental and computed values of R 2 ¼ 0.97 (Kopitz et al, 2008). In contrast to the nucleobases, the sugar-phosphate backbone of nucleic acids is more difficult to model using the approximation of fixed atomic charges.…”

Section: Recent Force Field and Simulation Methods Developmentsmentioning

confidence: 89%

Molecular recognition of RNA: challenges for modelling interactions and plasticity

Gohlke

2009

J of Molecular Recognition

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There is growing interest in molecular recognition processes of RNA because of RNA's widespread involvement in biological processes. Computational approaches are increasingly used for analysing and predicting binding to RNA, fuelled by encouraging progress in developing simulation, free energy and docking methods for nucleic acids. These developments take into account challenges regarding the energetics of RNA-ligand binding, RNA plasticity, and the presence of water molecules and ions in the binding interface. Accordingly, we will detail advances in force field and scoring function development for molecular dynamics (MD) simulations, free energy computations and docking calculations of nucleic acid complexes. Furthermore, we present methods that can detect moving parts within RNA structures based on graph-theoretical approaches or normal mode analysis (NMA). As an example of the successful use of these developments, we will discuss recent structure-based drug design approaches that focus on the bacterial ribosomal A-site RNA as a drug target.

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“…Crystal structures and thermochemical data also indicate for a favourable contribution of this interaction for stable RNA duplex formations using fluorinated nucleobases [53][54][55]. Such stabilising forces are observed in the X-ray crystal structure of 1 -deoxy-1 -(4-fluorophenyl)-β-d-ribofuranose (CSD entry: CUYWAU01).…”

Section: Fluorine In Multipolar Interactions To Electrophilic Residuesmentioning

confidence: 88%

“…H-C contacts are expected in 12-mer RNA duplexes of modified nucleobases with fluorine atoms at the Watson-Crick binding site [53]. In a recent study, Kopitz et al [55] investigated the stability of fluorobenzene-based RNA self-pairs with increasing fluorine substitution by a combined experimental and computational approach, again underscoring the importance of weak attractive C-F . .…”

Section: Fluorine In Multipolar Interactions To Electrophilic Residuesmentioning

confidence: 99%

Halogen…π Interactions as Important Contributors to Binding Affinity in Medicinal Chemistry

Matter

Nazaré

Güssregen

2012

The Importance of Pi‐Interactions in Crystal Engineering

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IntroductionMolecular recognition in biological systems relies on a sophisticated interplay of several nonbonded interactions between ligands and their binding sites in addition to other important factors like binding kinetics and desolvation. Insight into those interactions became possible due to the tremendous increase of 3D structural information of protein targets for medical therapy, as exemplified by the growth of the PDB database (RCSB [1,2]) with now ∼70 000 entries (December 2010). Detailed database analysis provides many structurally characterised examples for ligands favourably interacting with their target protein and thus allows studying the relevant interaction motifs contributing to the experimentally observed binding affinity. In addition, guidelines on favourable motifs can be deduced based on interaction geometries and associated affinity data [3].In order to identify lead structures for optimisation, biophysical and in silico lead finding techniques, like virtual screening [4][5][6][7] or structure-based design, are integral components in the industrial drug-discovery setting today and complementing the routinely applied highthroughput screening (HTS) [8,9]. Capitalising on 3D structural knowledge, computational approaches are cost effective and powerful, and can potentially reduce the number of in-vitro assays after in-silico selection to a few hundreds or thousands.

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Determinants of the Unexpected Stability of RNA Fluorobenzene Self Pairs

Cited by 39 publications

References 53 publications

Comparison of Intrinsic Stacking Energies of Ten Unique Dinucleotide Steps in A-RNA and B-DNA Duplexes. Can We Determine Correct Order of Stability by Quantum-Chemical Calculations?

Comparison of Intrinsic Stacking Energies of Ten Unique Dinucleotide Steps in A-RNA and B-DNA Duplexes. Can We Determine Correct Order of Stability by Quantum-Chemical Calculations?

Molecular recognition of RNA: challenges for modelling interactions and plasticity

Halogen…π Interactions as Important Contributors to Binding Affinity in Medicinal Chemistry

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