7 research outputs found

    QM Computations on Complete Nucleic Acids Building Blocks: Analysis of the Sarcin–Ricin RNA Motif Using DFT-D3, HF-3c, PM6-D3H, and MM Approaches

    No full text
    A set of conformations obtained from explicit solvent molecular dynamics (MD) simulations of the Sarcin–Ricin internal loop (SRL) RNA motif is investigated using quantum mechanical (QM, TPSS-D3/def2-TZVP DFT-D3) and molecular mechanics (MM, AMBER parm99bsc0+χ<sub>ol3</sub> force field) methods. Solvent effects are approximated using implicit solvent methods (COSMO for DFT-D3; GB and PB for MM). Large-scale DFT-D3 optimizations of the full 11-nucleotide motif are compared to MM results and reveal a higher flexibility of DFT-D3 over the MM in the optimization procedure. Conformational energies of the SRL motif expose significant differences in the DFT-D3 and MM energy descriptions that explain difficulties in MD simulations of the SRL motif. The TPSS-D3 data are in excellent agreement with results obtained by the hybrid functionals PW6B95-D3 and M06-2X. Computationally more efficient methods such as PM6-D3H and HF-3c show promising but partly inconsistent results. It is demonstrated that large-scale DFT-D3 computations on complete nucleic acids building blocks are a viable tool to complement the picture obtained from MD simulations and can be used as benchmarks for faster computational methods. Methodological challenges of large-scale QM computations on nucleic acids such as missing solvent–solute interactions and the truncation of the studied systems are discussed

    Why the Standard B3LYP/6-31G* Model Chemistry Should Not Be Used in DFT Calculations of Molecular Thermochemistry: Understanding and Correcting the Problem

    No full text
    We analyze the error compensations that are responsible for the relatively good performance of the popular B3LYP/6-31G* model chemistry for molecular thermochemistry. We present the B3LYP-gCP-D3/6-31G* scheme, which corrects for missing London dispersion and basis set superposition error (BSSE) in a physically sound manner. Benchmark results for the general main group thermochemistry, kinetics, and noncovalent interactions set (GMTKN30) are presented. A detailed look is cast on organic reactions of several arenes with C<sub>60</sub>, Diels–Alder reactions, and barriers to [4 + 3] cycloadditions. We demonstrate the practical advantages of the new B3LYP-gCP-D3/6-31G* scheme and show its higher robustness over standard B3LYP/6-31G*. B3LYP-gCP-D3/6-31G* is meant to fully substitute standard B3LYP/6-31G* calculations in the same black-box sense at essentially no increase in computational cost. The energy corrections are made available by a Web service (http://www.thch.uni-bonn.de/tc/gcpd3) and by freely available software

    Derivation of Reliable Geometries in QM Calculations of DNA Structures: Explicit Solvent QM/MM and Restrained Implicit Solvent QM Optimizations of G‑Quadruplexes

    No full text
    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

    MD and QM/MM Study of the Quaternary HutP Homohexamer Complex with mRNA, l‑Histidine Ligand, and Mg<sup>2+</sup>

    No full text
    The HutP protein from <i>B. subtilis</i> regulates histidine metabolism by interacting with an antiterminator mRNA hairpin in response to the binding of l-histidine and Mg<sup>2+</sup>. We studied the functional ligand-bound HutP hexamer complexed with two mRNAs using all-atom microsecond-scale explicit-solvent MD simulations performed with the Amber force fields. The experimentally observed protein-RNA interface exhibited good structural stability in the simulations with the exception of some fluctuations in an unusual adenine-threonine interaction involving two closely spaced H-bonds. We further investigated this interaction by comparing QM/MM and MM optimizations, using the QM region comprising almost 350 atoms described at the DFT-D3 level. The QM/MM method clearly improved the adenine-threonine interaction compared to MM, especially when the X–H bond lengths were frozen during the MM optimization to mimic the use of SHAKE in the MD simulations. Thus, both the MM approximation and the use of SHAKE can compromise the description of H-bonds at protein-RNA interfaces. The simulations also revealed a notable Mg<sup>2+</sup>-parameter dependence in the behavior of the ligand-binding pocket (LBP). With the SPC/E water model, the 12–6 Åqvist and Li&Merz parameters provided an entirely stable LBP structure, but the 12–6 Allnér and 12–6–4 Li&Merz parametrizations resulted in a progressive loss of direct nitrogen–Mg<sup>2+</sup> LBP coordination. The Allnér and Li&Merz 12–6 parametrizations were also tested with the TIP3P water model; the LBP was destabilized in both cases. This illustrates the difficulty of consistently describing different Mg<sup>2+</sup> interactions using nonpolarizable force fields. Overall, the simulations support the hypothesis that HutP protein becomes fully structured upon ligand binding. Subsequent RNA binding does not affect the protein structure, in keeping with the mechanism inferred from experimental structures

    MD and QM/MM Study of the Quaternary HutP Homohexamer Complex with mRNA, l‑Histidine Ligand, and Mg<sup>2+</sup>

    No full text
    The HutP protein from <i>B. subtilis</i> regulates histidine metabolism by interacting with an antiterminator mRNA hairpin in response to the binding of l-histidine and Mg<sup>2+</sup>. We studied the functional ligand-bound HutP hexamer complexed with two mRNAs using all-atom microsecond-scale explicit-solvent MD simulations performed with the Amber force fields. The experimentally observed protein-RNA interface exhibited good structural stability in the simulations with the exception of some fluctuations in an unusual adenine-threonine interaction involving two closely spaced H-bonds. We further investigated this interaction by comparing QM/MM and MM optimizations, using the QM region comprising almost 350 atoms described at the DFT-D3 level. The QM/MM method clearly improved the adenine-threonine interaction compared to MM, especially when the X–H bond lengths were frozen during the MM optimization to mimic the use of SHAKE in the MD simulations. Thus, both the MM approximation and the use of SHAKE can compromise the description of H-bonds at protein-RNA interfaces. The simulations also revealed a notable Mg<sup>2+</sup>-parameter dependence in the behavior of the ligand-binding pocket (LBP). With the SPC/E water model, the 12–6 Åqvist and Li&Merz parameters provided an entirely stable LBP structure, but the 12–6 Allnér and 12–6–4 Li&Merz parametrizations resulted in a progressive loss of direct nitrogen–Mg<sup>2+</sup> LBP coordination. The Allnér and Li&Merz 12–6 parametrizations were also tested with the TIP3P water model; the LBP was destabilized in both cases. This illustrates the difficulty of consistently describing different Mg<sup>2+</sup> interactions using nonpolarizable force fields. Overall, the simulations support the hypothesis that HutP protein becomes fully structured upon ligand binding. Subsequent RNA binding does not affect the protein structure, in keeping with the mechanism inferred from experimental structures

    Comparative Assessment of Different RNA Tetranucleotides from the DFT-D3 and Force Field Perspective

    No full text
    Classical force field (FF) molecular dynamics (MD) simulations of RNA tetranucleotides have substantial problems in reproducing conformer populations indicated by NMR experiments. To provide more information about the possible sources of errors, we performed quantum mechanical (QM, TPSS-D3/def2-TZVP) and molecular mechanics (MM, AMBER parm99bsc0+χ<sub>OL3</sub>) calculations of different r­(CCCC), r­(GACC), and r­(UUUU) conformers obtained from explicit solvent MD simulations. Solvent effects in the static QM and MM calculations were mimicked using implicit solvent models (COSMO and Poisson–Boltzmann, respectively). The comparison of QM and MM geometries and energies revealed that the two methodologies provide qualitatively consistent results in most of the cases. Even though we found some differences, these were insufficient to indicate any systematic corrections of the RNA FF terms that could improve the performance of classical MD in simulating tetranucleotides. On the basis of these findings, we inferred that the overpopulation of intercalated conformers in the MD simulations of RNA tetramers, which were not observed experimentally, might be predominantly caused by imbalanced water–solvent and water–water interactions. Apart from the large-scale QM calculations performed to assess the performance of the AMBER FF, a representative spectrum of faster QM methods was tested

    Quantum Chemical Benchmark Study on 46 RNA Backbone Families Using a Dinucleotide Unit

    No full text
    We have created a benchmark set of quantum chemical structure–energy data denoted as UpU46, which consists of 46 uracil dinucleotides (UpU), representing all known 46 RNA backbone conformational families. Penalty-function-based restrained optimizations with COSMO TPSS-D3/def2-TZVP ensure a balance between keeping the target conformation and geometry relaxation. The backbone geometries are close to the clustering-means of their respective RNA bioinformatics family classification. High-level wave function methods (DLPNO–CCSD­(T) as reference) and a wide-range of dispersion-corrected or inclusive DFT methods (DFT-D3, VV10, LC-BOP-LRD, M06-2X, M11, and more) are used to evaluate the conformational energies. The results are compared to the Amber RNA bsc0χ<sub>OL3</sub> force field. Most dispersion-corrected DFT methods surpass the Amber force field significantly in accuracy and yield mean absolute deviations (MADs) for relative conformational energies of ∼0.4–0.6 kcal/mol. Double-hybrid density functionals represent the most accurate class of density functionals. Low-cost quantum chemical methods such as PM6-D3H+, HF-3c, DFTB3-D3, as well as small basis set calculations corrected for basis set superposition errors (BSSEs) by the gCP procedure are also tested. Unfortunately, the presently available low-cost methods are struggling to describe the UpU conformational energies with satisfactory accuracy. The UpU46 benchmark is an ideal test for benchmarking and development of fast methods to describe nucleic acids, including force fields
    corecore