The highly accurate ab initio equilibrium geometry of the hydrogen‐bonded uracil dimer is derived using a composite geometry extrapolation scheme based on all‐electron, complete basis set ...extrapolated Møller–Plesset perturbation theory using the jun‐pwCVT,QZ basis sets combined with a valence CCSD(T)/cc‐pVTZ high‐level correction. Geometrical changes on dimerization are discussed and the performance of the several density functional approximations (among others SCAN, ωB97M‐V, DSD‐PBEP86‐D3(BJ), and DSD‐PBEP86‐NL) is evaluated. Orbital‐optimized MP2.5 is discussed as a reduced‐cost alternative to the CCSD(T) gradient in the composite scheme. A new reference interaction energy is calculated with explicitly correlated F12‐CCSD(T).
Based on a cost‐effective composite gradient approach the structural features of the uracil dimerization are presented with quantum chemical “gold‐standard” accuracy. Highly accurate interaction and deformation energies are obtained. The performance of various lower levels of theories for the structure and energies are evaluated.
Phosphate···π, also called anion···π, contacts occur between nucleobases and anionic phosphate oxygens (OP2) in r(GNRA) and r(UNNN) U-turn motifs (N = A,G,C,U; R = A,G). These contacts were ...investigated using state-of-the-art quantum-chemical methods (QM) to characterize their physicochemical properties and to serve as a reference to evaluate AMBER force field (AFF) performance. We found that phosphate···π interaction energies calculated with the AFF for dimethyl phosphate···nucleobase model systems are less stabilizing in comparison with double-hybrid DFT and that minimum contact distances are larger for all nucleobases. These distance stretches are also observed in large-scale AFF vs QM/MM computations and classical molecular dynamics (MD) simulations on several r(gcGNRAgc) tetraloop hairpins when compared to experimental data extracted from X-ray/cryo-EM structures (res. ≤ 2.5 Å) using the WebFR3D bioinformatic tool. MD simulations further revealed shifted OP2/nucleobase positions. We propose that discrepancies between the QM and AFF result from a combination of missing polarization in the AFF combined with too large AFF Lennard-Jones (LJ) radii of nucleobase carbon atoms in addition to an exaggerated short-range repulsion of the
LJ repulsive term. We compared these results with earlier data gathered on lone pair···π contacts in CpG Z-steps occurring in r(UNCG) tetraloops. In both instances, charge transfer calculations do not support any significant
→ π* donation effects. We also investigated thiophosphate···π contacts that showed reduced stabilizing interaction energies when compared to phosphate···π contacts. Thus, we challenge suggestions that the experimentally observed enhanced thermodynamic stability of phosphorothioated r(GNRA) tetraloops can be explained by larger London dispersion.
Although atomistic explicit-solvent Molecular Dynamics (MD) is a popular tool to study protein-RNA recognition, satisfactory MD description of protein-RNA complexes is not always achieved. ...Unfortunately, it is often difficult to separate MD simulation instabilities primarily caused by the simple point-charge molecular mechanics (MM) force fields from problems related to the notorious uncertainties in the starting structures. Herein, we report a series of large-scale QM/MM calculations on the U1A protein-RNA complex. This experimentally well-characterized system has an intricate protein-RNA interface, which is very unstable in MD simulations. The QM/MM calculations identify several H-bonds poorly described by the MM method and thus indicate the sources of instabilities of the U1A interface in MD simulations. The results suggest that advanced QM/MM computations could be used to indirectly rationalize problems seen in MM-based MD simulations of protein-RNA complexes. As the most accurate QM method, we employ the computationally demanding meta-GGA density functional TPSS-D3(BJ)/def2-TZVP level of theory. Because considerably faster methods would be needed to extend sampling and to study even larger protein-RNA interfaces, a set of low-cost QM/MM methods is compared to the TPSS-D3(BJ)/def2-TZVP data. The PBEh-3c and B97-3c density functional composite methods appear to be suitable for protein-RNA interfaces. In contrast, HF-3c and the tight-binding Hamiltonians DFTB3-D3 and GFN-xTB perform unsatisfactorily and do not provide any advantage over the MM description. These conclusions are supported also by similar analysis of a simple HutP protein-RNA interface, which is well-described by MD with the exception of just one H-bond. Some other methodological aspects of QM/MM calculations on protein-RNA interfaces are discussed.
Pseudouridine is the most frequently naturally occurring RNA modification, found in all classes of biologically functional RNAs. Compared to uridine, pseudouridine contains an additional hydrogen ...bond donor group and is therefore widely regarded as a structure stabilizing modification. However, the effects of pseudouridine modifications on the structure and dynamics of RNAs have so far only been investigated in a limited number of different structural contexts. Here, we introduced pseudouridine modifications into the U-turn motif and the adjacent U:U closing base pair of the neomycin-sensing riboswitch (NSR)-an extensively characterized model system for RNA structure, ligand binding, and dynamics. We show that the effects of replacing specific uridines with pseudouridines on RNA dynamics crucially depend on the exact location of the replacement site and can range from destabilizing to locally or even globally stabilizing. By using a combination of NMR spectroscopy, MD simulations and QM calculations, we rationalize the observed effects on a structural and dynamical level. Our results will help to better understand and predict the consequences of pseudouridine modifications on the structure and function of biologically important RNAs.
Modern dispersion-corrected DFT methods have made it possible to perform reliable QM studies on complete nucleic acid (NA) building blocks having hundreds of atoms. Such calculations, although still ...limited to investigations of potential energy surfaces, enhance the portfolio of computational methods applicable to NAs and offer considerably more accurate intrinsic descriptions of NAs than standard MM. However, in practice such calculations are hampered by the use of implicit solvent environments and truncation of the systems. Conventional QM optimizations are spoiled by spurious intramolecular interactions and severe structural deformations. Here we compare two approaches designed to suppress such artifacts: partially restrained continuum solvent QM and explicit solvent QM/MM optimizations. We report geometry relaxations of a set of diverse double-quartet guanine quadruplex (GQ) DNA stems. Both methods provide neat structures without major artifacts. However, each one also has distinct weaknesses. In restrained optimizations, all errors in the target geometries (i.e., low-resolution X-ray and NMR structures) are transferred to the optimized geometries. In QM/MM, the initial solvent configuration causes some heterogeneity in the geometries. Nevertheless, both approaches represent a decisive step forward compared to conventional optimizations. We refine earlier computations that revealed sizable differences in the relative energies of GQ stems computed with AMBER MM and QM. We also explore the dependence of the QM/MM results on the applied computational protocol.
Abstract
The neomycin sensing riboswitch is the smallest biologically functional RNA riboswitch, forming a hairpin capped with a U-turn loop-a well-known RNA motif containing a conserved uracil. It ...was shown previously that a U→C substitution of the eponymous conserved uracil does not alter the riboswitch structure due to C protonation at N3. Furthermore, cytosine is evolutionary permitted to replace uracil in other U-turns. Here, we use molecular dynamics simulations to study the molecular basis of this substitution in the neomycin sensing riboswitch and show that a structure-stabilizing monovalent cation-binding site in the wild-type RNA is the main reason for its negligible structural effect. We then use NMR spectroscopy to confirm the existence of this cation-binding site and to demonstrate its effects on RNA stability. Lastly, using quantum chemical calculations, we show that the cation-binding site is altering the electronic environment of the wild-type U-turn so that it is more similar to the cytosine mutant. The study reveals an amazingly complex and delicate interplay between various energy contributions shaping up the 3D structure and evolution of nucleic acids.
The simplest molecule with a disulfide bond, hydrogen disulfide (HSSH), represents an ideal test model for the determination of accurate gas-phase equilibrium structures for molecules containing ...third-row elements. First, pure theoretical composite schemes based on the coupled-cluster (CC) theory, which take into account the extrapolation to the complete basis set limit, core-valence correlation contributions, higher excitations in the CC expansion, and relativistic effects, allow for calculating accurate reference geometrical parameters. Second, using experimental vibrational ground-state rotational constants for a set of isotopologues, in conjunction with vibrational corrections based on second-order vibrational perturbation theory formulation and the recently developed Molecular Structure Refinement (MSR) software, we have determined the semi-experimental (SE) equilibrium structure of HSSH. The comparison of SE parameters with the computational best estimates shows an agreement within 0.001 Å for distances and 0.1° for angles, thus further validating the SE approach as cost-effective, provided that the required experimental data are available. Together with the intrinsic interest of HSSH, also in connection with astrochemistry, highly accurate structural properties of a prototypical disulfide bond can serve as references for future studies of larger molecules of biological interest containing this challenging moiety.
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•Theoretical equilibrium structure from composite schemes.•Semi-experimental equilibrium structure.•Disulfide bond length determined with 1 mÅ accuracy.
Cyclobutane pyrimidine dimers (CpDs) are among the most common DNA lesions occurring due to the interaction with ultraviolet light. While photolyases have been well known as external factors ...repairing CpDs, the intrinsic self-repairing capabilities of the GATdouble bond, length as m-dashT DNA sequence were discovered only recently and are still largely obscure. Here, we elucidate the mechanistic details of this self-repair process by means of MD simulations and QM/MM computations involving the algebraic diagrammatic construction to the second order ADC(2) method. We show that local UV-excitation of guanine may be followed by up to three subsequent electron transfers, which may eventually enable efficient CpD ring opening when the negative charge resides on the Tdouble bond, length as m-dashT dimer. Consequently, the molecular mechanism of GATdouble bond, length as m-dashT self-repair can be envisaged as sequential electron transfer (SET) occurring downhill along the slope of the S
potential energy surface. Even though the general features of the SET mechanism are retained in both of the studied stacked conformers, our optimizations of different S
/S
state crossings revealed minor differences which could influence their self-repair efficiencies. We expect that such assessment of the availability and efficiency of the SET process in other DNA oligomers could hint towards other sequences exhibiting similar photochemical properties. Such explorations will be particularly fascinating in the context of the origins of biomolecules on Earth, owing to the lack of external repairing factors in the Archean age.
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