Arnošt Mládek

Refinement of the Cornell et al. Nucleic acids force field based on reference quantum chemical calculations of glycosidic torsion profiles

We report a reparameterization of the glycosidic torsion χ of the Cornell et al. AMBER force field for RNA, χOL. The parameters remove destabilization of the anti region found in the ff99 force field and thus prevent formation of spurious ladder-like structural distortions in RNA simulations. They also improve the description of the syn region and the syn–anti balance as well as enhance MD simulations of various RNA structures. Although χOL can be combined with both ff99 and ff99bsc0, we recommend the latter. We do not recommend using χOL for B-DNA because it does not improve upon ff99bsc0 for canonical structures. However, it might be useful in simulations of DNA molecules containing syn nucleotides. Our parametrization is based on high-level QM calculations and differs from conventional parametrization approaches in that it incorporates some previously neglected solvation-related effects (which appear to be essential for obtaining correct anti/high-anti balance). Our χOL force field is compared with several previous glycosidic torsion parametrizations.

Nature and magnitude of aromatic base stacking in DNA and RNA: Quantum chemistry, molecular mechanics, and experiment

Base stacking is a major interaction shaping up and stabilizing nucleic acids. During the last decades, base stacking has been extensively studied by experimental and theoretical methods. Advanced quantum-chemical calculations clarified that base stacking is a common interaction, which in the first approximation can be described as combination of the three most basic contributions to molecular interactions, namely, electrostatic interaction, London dispersion attraction and short-range repulsion. There is not any specific π-π energy term associated with the delocalized π electrons of the aromatic rings that cannot be described by the mentioned contributions. The base stacking can be rather reasonably approximated by simple molecular simulation methods based on well-calibrated common force fields although the force fields do not include nonadditivity of stacking, anisotropy of dispersion interactions, and some other effects. However, description of stacking association in condensed phase and understanding of the stacking role in biomolecules remain a difficult problem, as the net base stacking forces always act in a complex and context-specific environment. Moreover, the stacking forces are balanced with many other energy contributions. Differences in definition of stacking in experimental and theoretical studies are explained.

The DNA and RNA sugar–phosphate backbone emerges as the key player. An overview of quantum-chemical, structural biology and simulation studies

Knowledge of geometrical and physico-chemical properties of the sugar-phosphate backbone substantially contributes to the comprehension of the structural dynamics, function and evolution of nucleic acids. We provide a side by side overview of structural biology/bioinformatics, quantum chemical and molecular mechanical/simulation studies of the nucleic acids backbone. We highlight main features, advantages and limitations of these techniques, with a special emphasis given to their synergy. The present status of the research is then illustrated by selected examples which include classification of DNA and RNA backbone families, benchmark structure-energy quantum chemical calculations, parameterization of the dihedral space of simulation force fields, incorporation of arsenate into DNA, sugar-phosphate backbone self-cleavage in small RNA enzymes, and intricate geometries of the backbone in recurrent RNA building blocks. Although not apparent from the current literature showing limited overlaps between the QM, simulation and bioinformatics studies of the nucleic acids backbone, there in fact should be a major cooperative interaction between these three approaches in studies of the sugar-phosphate backbone.

Can We Accurately Describe the Structure of Adenine Tracts in B-DNA? Reference Quantum-Chemical Computations Reveal Overstabilization of Stacking by Molecular Mechanics.

Sequence-dependent local variations of helical parameters, structure, and flexibility are crucial for molecular recognition processes involving B-DNA. A-tracts, i.e., stretches of several consecutive adenines in one strand that are in phase with the DNA helical repeat, mediate significant DNA bending. During the past few decades, there have been intense efforts to understand the sequence dependence of helical parameters in DNA. Molecular dynamics (MD) simulations can provide valuable insights into the molecular mechanism behind the relationship between sequence and structure. However, although recent improvements in empirical force fields have helped to capture many sequence-dependent B-DNA properties, several problems remain, such as underestimation of the helical twist and suspected underestimation of the propeller twist in A-tracts. Here, we employ reference quantum mechanical (QM) calculations, explicit solvent MD, and bioinformatics to analyze the underestimation of propeller twisting of A-tracts in simulations. Although we did not identify a straightforward explanation, we discovered two imbalances in the empirical force fields. The first was overestimation of stacking interactions accompanied by underestimation of base-pairing energy, which we attribute to anisotropic polarizabilities that are not reflected by the isotropic force fields. This may lead to overstacking with potentially important consequences for MD simulations of nucleic acids. The second observed imbalance was steric clash between A(N1) and T(N3) nitrogens of AT base pairs in force-field descriptions, resulting in overestimation of the AT pair stretch in MD simulations. We also substantially extend the available set of benchmark estimated CCSD(T)/CBS data for B-DNA base stacking and provide a code that allows the generation of diverse base-stacking geometries suitable for QM computations with predefined intra- and interbase pair parameters.

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

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 bsc0χOL3 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.

Ion Binding to Quadruplex DNA Stems. Comparison of MM and QM Descriptions Reveals Sizable Polarization Effects Not Included in Contemporary Simulations

Molecular mechanical (MM) force fields are commonly employed for biomolecular simulations. Despite their success, the nonpolarizable nature of contemporary additive force fields limits their performance, especially in long simulations and when strong polarization effects are present. Guanine quadruplex D(R)NA molecules have been successfully studied by MM simulations in the past. However, the G-stems are stabilized by a chain of monovalent cations that create sizable polarization effects. Indeed, simulation studies revealed several problems that have been tentatively attributed to the lack of polarization. Here, we provide a detailed comparison between quantum chemical (QM) DFT-D3 and MM potential energy surfaces of ion binding to G-stems and assess differences that may affect MM simulations. We suggest that MM describes binding of a single ion to the G-stem rather well. However, polarization effects become very significant when a second ion is present. We suggest that the MM approximation substantially limits accuracy of description of energy and dynamics of multiple ions inside the G-stems and binding of ions at the stem-loop junctions. The difference between QM and MM descriptions is also explored using symmetry-adapted perturbation theory and quantum theory of atoms in molecules analyses, which reveal a delicate balance of electrostatic and induction effects.

How to understand quantum chemical computations on DNA and RNA systems? A practical guide for non-specialists

In this review primarily written for non-experts we explain basic methodological aspects and interpretation of modern quantum chemical (QM) computations applied to nucleic acids. We introduce current reference QM computations on small model systems consisting of dozens of atoms. Then we comment on recent advance of fast and accurate dispersion-corrected density functional theory methods, which will allow computations of small but complete nucleic acids building blocks in the near future. The qualitative difference between QM and molecular mechanics (MM, force field) computations is discussed. We also explain relation of QM and molecular simulation computations to experiments.

On the Road from Formamide Ices to Nucleobases: IR-Spectroscopic Observation of a Direct Reaction between Cyano Radicals and Formamide in a High-Energy Impact Event

The formamide-based synthesis of nucleic acids is considered as a nonaqueous scenario for the emergence of biomolecules from inorganic matter. In the current study, we scrutinized the chemical composition of formamide ices mixed with an FeNi meteorite material treated with laser-induced dielectric breakdown plasma created in nitrogen buffer gas. These experiments aimed to capture the first steps of those chemical transformations that may lead to the formation of nucleobases during the impact of an extraterrestrial icy body containing formamide on an early Earth atmosphere. High-resolution FT-IR spectroscopy combined with quantum chemical calculations was used to analyze the volatile fraction of the products formed during such an event. We have found that the spectrum of the evaporated formamide ices is dominated by the spectral signatures of the dimeric form of formamide. Upon exposure to laser sparks, new well-defined bands appear in the spectrum centered at ~820, ~995, and ~1650 cm(-1). On the basis of quantum chemical calculations, these bands can be assigned to the absorptions of 2-amino-2-hydroxy-acetonitrile and to 2-amino-2-hydroxy-malononitrile, which are formed in a direct reaction between formamide and CN(•) radicals upon the high-energy impact event. We also show that there is an exergonic reaction route via these intermediates leading to diaminomaleonitrile, which is generally considered to play a key role in the synthesis of nucleobases.

Benchmark quantum-chemical calculations on a complete set of rotameric families of the DNA sugar–phosphate backbone and their comparison with modern density functional theory

The DNA sugar-phosphate backbone has a substantial influence on the DNA structural dynamics. Structural biology and bioinformatics studies revealed that the DNA backbone in experimental structures samples a wide range of distinct conformational substates, known as rotameric DNA backbone conformational families. Their correct description is essential for methods used to model nucleic acids and is known to be the Achilles heel of force field computations. In this study we report the benchmark database of MP2 calculations extrapolated to the complete basis set of atomic orbitals with aug-cc-pVTZ and aug-cc-pVQZ basis sets, MP2(T,Q), augmented by ΔCCSD(T)/aug-cc-pVDZ corrections. The calculations are performed in the gas phase as well as using a COSMO solvent model. This study includes a complete set of 18 established and biochemically most important families of DNA backbone conformations and several other salient conformations that we identified in experimental structures. We utilize an electronically sufficiently complete DNA sugar-phosphate-sugar (SPS) backbone model system truncated to prevent undesired intramolecular interactions. The calculations are then compared with other QM methods. The BLYP and TPSS functionals supplemented with Grimmes D3(BJ) dispersion term provide the best tradeoff between computational demands and accuracy and can be recommended for preliminary conformational searches as well as calculations on large model systems. Among the tested methods, the best agreement with the benchmark database has been obtained for the double-hybrid DSD-BLYP functional in combination with a quadruple-ζ basis set, which is, however, computationally very demanding. The new hybrid density functionals PW6B95-D3 and MPW1B95-D3 yield outstanding results and even slightly outperform the computationally more demanding PWPB95 double-hybrid functional. B3LYP-D3 is somewhat less accurate compared to the other hybrids. Extrapolated MP2(D,T) calculations are not as accurate as the less demanding DFT-D3 methods. Preliminary force field tests using several charge sets reveal an almost order of magnitude larger deviations from the reference QM data compared to modern DFT-D3, underlining the challenges facing force field simulations of nucleic acids. As expected, inclusion of the solvent environment approximated by a continuum approach has a large impact on the relative stabilities of different backbone substates and is important when comparing the QM data with structural bioinformatics and other experimental data.

Formamide-based prebiotic synthesis of nucleobases: a kinetically accessible reaction route.

Synthesis of nucleobases in nonaqueous environments is an alternative way for the emergence of terrestrial life, which could solve the fundamental problem connected to the hydrolytic instability of nucleic acid components in an aqueous environment. In this contribution, we present a plausible reaction route for the prebiotic synthesis of nucleobases in formamide, which does not require participation of the formamide trimer and aminoimidazole-carbonitrile intermediates. The computed activation energy of the proposed pathway is noticeably higher than that of the HCN-based synthetic route, but it is still feasible under the experimental conditions of the Saladino synthesis. We show that, albeit both the pyrimidine and purine ring formation utilizes the undissociated form of formamide, the dehydration product of formamide, HCN, may also play a key role in the mechanism. The rate determining step of the entire reaction path is the cyclization of the diaza-pentanimine precursor. The subsequent formation of the imidazole ring proceeds with a moderate activation energy. Our calculations thus demonstrate that the experimentally suggested reaction path without the involvement of aminoimidazole-carbonitrile intermediates is also a viable alternative for the nonaqueous synthesis of nucleobases.