Stacking geometry between two sheared Watson-Crick basepairs: Computational chemistry and bioinformatics based prediction (original) (raw)
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The Journal of Physical Chemistry A, 2005
Large RNA molecules exhibit an astonishing variability of base-pairing patterns, while many of the RNA base-pairing families have no counterparts in DNA. The cis Watson-Crick/sugar edge (cis WC/SE) RNA base pairing is investigated by ab initio quantum chemical calculations. A detailed structural and energetic characterization of all 13 crystallographically detected members of this family is provided by means of B3LYP/ 6-31G** and RIMP2/aug-cc-pVDZ calculations. Further, a prediction is made for the remaining 3 cis WC/ SE base pairs which are yet to be seen in the experiments. The interaction energy calculations point at the key role of the 2′-OH group in stabilizing the sugar-base contact and predict all 16 cis WC/SE base-pairing patterns to be nearly isoenergetic. The perfect correlation of the main geometrical parameters in the gasphase optimized and X-ray structures shows that the principle of isosteric substitutions in RNA is rooted from the intrinsic structural similarity of the isolated base pairs. The present quantum chemical calculations for the first time analyze base pairs involving the ribose 2′-OH group and unambiguously correlate the structural information known from experiments with the energetics of interactions. The calculations further show that the relative importance and absolute value of the dispersion energy in the cis WC/SE base pairs are enhanced compared to the standard base pairs. This may by an important factor contributing to the strength of such interactions when RNA folds in its polar environment. The calculations further demonstrate that the Cornell et al. force field commonly used in molecular modeling and simulations provides satisfactory performance for this type of RNA interactions. * Corresponding
Motifs in nucleic acids: Molecular mechanics restraints for base pairing and base stacking
Journal of Computational Chemistry, 2003
In building and refining nucleic acid structures, it is often desirable to enforce particular base pairing and/or base stacking interactions. Energy-based modeling programs with classical molecular mechanics force fields do not lend themselves to the easy imposition of penalty terms corresponding to such restraints, because the requirement that two bases lie in or near the same plane (pairing) or that they lie in parallel planes (stacking) cannot be easily expressed in terms of traditional interactions involving two atoms (bonds), three atoms (angles), or four atoms (torsions). Here we derive expressions that define a collection of pseudobonds and pseudoangles through which molecular mechanics restraints for base pairing and stacking can be imposed. We have implemented these restraints into the JUMNA package for modeling DNA and RNA structures. JUMNA scripts can specify base pairing with a variety of standard geometries (Watson-Crick, Hoogsteen, wobble, etc.), or with user-defined geometries; they can also specify stacking arrangements. We have also implemented "soft-core" functions to modify van der Waals and electrostatic interactions to avoid steric conflicts in particularly difficult refinements where two backbones need to pass through one another. Test cases are presented to show the utility of the method. The restraints could be adapted for implementation in other molecular mechanics packages.
The Journal of Physical Chemistry B, 2009
Trans Hoogsteen/sugar edge (H/SE) RNA base pairs form one of the six families of RNA base pairs that utilize the 2′-hydroxyl group of ribose for base pairing and play key roles in stabilizing folded RNA molecules. Here, we provide a detailed quantum chemical characterization of intrinsic structures and interaction energies of this base pair family, along with the evaluation of solvent screening effects by a continuum solvent approach. We report DFT-optimized geometries and MP2 interaction energies for all 10 crystallographically identified members of the family, for a representative set of them, using complete basis set extrapolation. For 6 of the 10 base pairs, we had to apply geometric constraints to keep the geometries relevant to RNA. We confirm that the remaining, hitherto undetected, possible members of this family do not have appropriate steric features required to establish stable base pairing in the trans H/SE fashion. The interaction patterns in the trans H/SE family are highly diverse, with gas-phase interaction energies in the range from-1 to-17 kcal/mol. Except for the C/rC and G/rG trans H/SE base pairs, the interaction energy is roughly evenly distributed between the HF and correlation components. Thus, in the trans H/SE base pairs, the relative importance of electron correlation is noticeably smaller than in the cis WC/SE or cis and trans SE/SE base pairs, but still larger than in canonical base pairs. The trans H/SE A/rG base pair is the intrinsically most stable member of this family. This base pair is also known as the sheared AG base pair and belongs to the most prominent set of RNA base pairs utilized in molecular building blocks of functional RNAs. For all trans H/SE base pairs that we identified, in addition to conventional base pairing, viable alternative structures were stabilized by amino-acceptor interactions. In the QM calculations, these amino-acceptor complexes appear to be equally as stable as those with common H-bonds, and more importantly, the switch to amino-acceptor interaction does not require any significant geometrical rearrangement of the base pairs. Such interactions are worthy of further investigations, as X-ray crystallography cannot unambiguously distinguish between conventional and amino-acceptor interactions involving the 2′-hydroxyl group, formation of such interactions is usually not considered, and molecular modeling force fields do not include such interactions properly as a result of neglect of aminogroup pyramidalization.
Theoretical analysis of noncanonical base pairing interactions in RNA molecules
Journal of …, 2007
Noncanonical base pairs in RNA have strong structural and functional implications but are currently not considered for secondary structure predictions. We present results of comparative ab initio studies of stabilities and interaction energies for the three standard and 24 selected unusual RNA base pairs reported in the literature. Hydrogen added models of isolated base pairs, with heavy atoms frozen in their ‘away from equilibrium’ geometries, built from coordinates extracted from NDB, were geometry optimized using HF/6-31G** basis set, both before and after unfreezing the heavy atoms. Interaction energies, including BSSE and deformation energy corrections, were calculated, compared with respective single point MP2 energies, and correlated with occurrence frequencies and with types and geometries of hydrogen bonding interactions. Systems having two or more N-H...O/N hydrogen bonds had reasonable interaction energies which correlated well with respective occurrence frequencies and highlighted the possibility of some of them playing important roles in improved secondary structure prediction methods. Several of the remaining base pairs with one N-H...O/N and/or one C-H...O/N interactions respectively, had poor interaction energies and negligible occurrences. High geometry variations on optimization of some of these were suggestive of their conformational switch like characteristics.
Theoretical analysis of noncanonical base pairs in RNA molecules
2006
Noncanonical base pairs in RNA have strong structural and functional implications but are currently not considered for secondary structure predictions. We present results of comparative ab initio studies of stabilities and interaction energies for the three standard and 24 selected unusual RNA base pairs reported in the literature. Hydrogen added models of isolated base pairs, with heavy atoms frozen in their 'away from equilibrium' geometries, built from coordinates extracted from NDB, were geometry optimized using HF/6-31G** basis set, both before and after unfreezing the heavy atoms. Interaction energies, including BSSE and deformation energy corrections, were calculated, compared with respective single point MP2 energies, and correlated with occurrence frequencies and with types and geometries of hydrogen bonding interactions. Systems having two or more N-H…O/N hydrogen bonds had reasonable interaction energies which correlated well with respective occurrence frequencies and highlighted the possibility of some of them playing important roles in improved secondary structure prediction methods. Several of the remaining base pairs with one N-H…O/N and/or one C-H…O/N interactions respectively, had poor interaction energies and negligible occurrences. High geometry variations on optimization of some of these were suggestive of their conformational switch like characteristics. [Bhattacharyya D, Koripella S C, Mitra A, Rajendran V B and Sinha B 2007 Theoretical analysis of noncanonical base pairing interactions in RNA molecules; J. Biosci. 32 809-825]
Journal of molecular modeling, 2017
Asymmetric bulge loop motifs are widely dispersed in all types of functional RNAs. They are frequently occurring structural motifs in folded RNA structures and appear commonly in pre-microRNA and ribosomes, where they are involved in specific RNA-RNA and RNA-protein interactions. It is therefore necessary to understand such motifs from a structural point of view. We analyzed all available RNA structures and identified quite a few fragments of double helices that contain bulges. We found that these discontinuities often introduce kinks into the double helices, which also affects the stacking overlap between the base pairs across the irregularity. In order to understand the influence of these bulges on stability and flexibility, we carried out molecular dynamics simulations of three different single-residue bulge-containing RNA helices using the CHARMM36 force field. The structural variability at the junctions of RNA bulges is expected to differ from that in continuous double-helical ...
Journal of Molecular Biology, 1997
The solution structure of the RNA duplex (rGGGCUGAAGCCCU), containing tandem G.A mismatches has been determined by NMR spectroscopy and restrained molecular dynamics. A homonuclear 3D TOCSY-NOESY was used to derive 18 to 30 distance restraints per nucleotide, as well as all gamma torsion angles and sugar puckers for the central UGAA part of the molecule. Using these constraints, together with cross-strand distances, involving exchangeable imino protons, and essentially all other torsion angles that can accurately be determined (i.e. beta, epsilon) otherwise, the structure of the UGAA domain could be determined with high precision (r.m.s.d. 0.62 A), without the aid of isotopically enriched RNA. The G.A base-pairs are of the sheared pairing type, with both nucleotides in the anti conformation, and hydrogen bonds between the guanine 2-amino and the adenine N7 and between the guanine N3 and the adenine 6-amino. Surprisingly the sugar of the guanosine of the G.A. mismatch adopts a 2'-endo sugar pucker conformation. Comparison with other RNA structures, in which two such G.A base-pairs are formed reveals that this detailed structure depends on the identity of the base 5' to the guanosine in the tandem G.A base-pairs. A geometrical model for the incorporation of sheared tandem G.A base-pairs in A-form helices is formulated, which explains the distinct different stacking properties and helical parameters in sequences containing tandem, sheared G.A base-pairs.
Journal of Molecular Biology, 2003
X-ray, phylogenetic and quantum chemical analysis of molecular interactions and conservation patterns of cis Watson -Crick (W.C.) A/G basepairs in 16 S rRNA, 23 S rRNA and other molecules was carried out. In these base-pairs, the A and G nucleotides interact with their W.C. edges with glycosidic bonds oriented cis relative to each other. The base-pair is stabilised by two hydrogen bonds, the C1 0 -C1 0 distance is enlarged and the G(N2) amino group is left unpaired. Quantum chemical calculations show that, in the absence of other interactions, the unpaired amino group is substantially non-planar due to its partial sp 3 pyramidalization, while the whole base-pair is internally propeller twisted and very flexible. The unique molecular properties of the cis W.C. A/G base-pairs make them distinct from other base-pairs. They occur mostly at the ends of canonical helices, where they serve as interfaces between the helix and other motifs. The cis W.C. A/G base-pairs play crucial roles in natural RNA structures with salient sequence conservation patterns. The key contribution to conservation is provided by the unpaired G(N2) amino group that is involved in a wide range of tertiary and neighbor contacts in the crystal structures. Many of them are oriented out of the plane of the guanine base and utilize the partial sp 3 pyramidalization of the G(N2).