Coarse-Grain Simulations of Skin Ceramide NS with Newly Derived Parameters Clarify Structure of Melted Phase

Ceramides are lipids that are involved in numerous biologically important structures (e.g., the stratum corneum and ceramide-rich platforms) and processes (e.g., signal transduction and membrane fusion), but their behavior is not fully understood. We report coarse-grain force field parameters for <i>N</i>-lignocerylsphingosine (ceramide NS, also known as ceramide 2) that are consistent with the Martini force field. These parameters were optimized for simulations in the gel phase and validated against atomistic simulations. Coarse-grained simulations with our parameters provide areas per lipid, membrane thicknesses, and electron density profiles that are in good agreement with atomistic simulations. Properties of the simulated membranes are compared with available experimental data. The obtained parameters were used to model the phase behavior of ceramide NS as a function of temperature and hydration. At low water content and above the main phase transition temperature, the bilayer melts into an irregular phase, which may correspond to the unstructured melted-chain phase observed in X-ray diffraction experiments. The developed parameters also reproduce the extended conformation of ceramide, which may occur in the stratum corneum. The parameters presented herein will facilitate studies on important complex functional structures such as the uppermost layer of the skin and ceramide-rich platforms in phospholipid membranes

A- to B‑DNA Transition in AMBER Force Fields and Its Coupling to Sugar Pucker

The A/B transition is a basic element of DNA conformational change. Because of its involvement in the sensing of the ionic conditions by DNA and in specific protein–DNA interactions, this transition is important for biological functions of DNA. Therefore, accurate modeling of the A/B equilibrium by means of empirical force fields is of utmost interest. In this work, we examine the A/B equilibrium in three AMBER force fields, including the recent bsc1 and OL15 modifications, using much longer MD simulations than attempted before. Special attention is paid to the coupling of the A/B equilibrium with the south/north (S/N) transition of the sugar pucker. We found that none of the tested force fields provided a satisfactory description of the A/B equilibrium because the B-form was predicted to be much too stable and the A-form was predicted to be almost absent even in concentrated trifluoroethanol solutions. Based on comparison with NMR data for duplexes and single nucleosides, we hypothesize that this problem arose from the incorrect description of the S/N equilibrium of sugar pucker, where the south conformation is much too stable, thus stabilizing the B-form. Because neither the A/B equilibrium in duplexes nor the S/N equilibrium in nucleosides was described accurately, further refinements of the AMBER DNA force fields are needed

Base Pair Fraying in Molecular Dynamics Simulations of DNA and RNA

Terminal base pairs of DNA and RNA molecules in solution are known to undergo frequent transient opening events (fraying). Accurate modeling of this process is important because of its involvement in nucleic acid end recognition and enzymatic catalysis. In this article, we describe fraying in molecular dynamics simulations with the ff99bsc0, ff99bsc0χ_OL3, and ff99bsc0χ_OL4 force fields, both for DNA and RNA molecules. Comparison with the experiment showed that while some features of fraying are consistent with the available data, others indicate potential problems with the force field description. In particular, multiple noncanonical structures are formed at the ends of the DNA and RNA duplexes. Among them are tWC/sugar edge pair, C–H edge/Watson–Crick pair, and stacked geometries, in which the terminal bases are stacked above each other. These structures usually appear within the first tens to hundreds of nanoseconds and substantially limit the usefulness of the remaining part of the simulation due to geometry distortions that are transferred to several neighboring base pairs (“end effects”). We show that stability of the noncanonical structures in ff99bsc0 may be partly linked to inaccurate glycosidic (χ) torsion potentials that overstabilize the <i>syn</i> region and allow for rapid <i>anti</i> to <i>syn</i> transitions. The RNA refined glycosidic torsion potential χ_OL3 provides an improved description and substantially more stable MD simulations of RNA molecules. In the case of DNA, the χ_OL4 correction gives only partial improvement. None of the tested force fields provide a satisfactory description of the terminal regions, indicating that further improvement is needed to achieve realistic modeling of fraying in DNA and RNA molecules

A Novel Approach for Deriving Force Field Torsion Angle Parameters Accounting for Conformation-Dependent Solvation Effects

A procedure for deriving force field torsion parameters including certain previously neglected solvation effects is suggested. In contrast to the conventional in vacuo approaches, the dihedral parameters are obtained from the difference between the quantum-mechanical self-consistent reaction field and Poisson–Boltzmann continuum solvation models. An analysis of the solvation contributions shows that two major effects neglected when torsion parameters are derived in vacuo are (i) conformation-dependent solute polarization and (ii) solvation of conformation-dependent charge distribution. Using the glycosidic torsion as an example, we demonstrate that the corresponding correction for the torsion potential is substantial and important. Our approach avoids double counting of solvation effects and provides parameters that may be used in combination with any of the widely used nonpolarizable discrete solvent models, such as TIPnP or SPC/E, or with continuum solvent models. Differences between our model and the previously suggested solvation models are discussed. Improvements were demonstrated for the latest AMBER RNA χ_OL3 parameters derived with inclusion of solvent effects in a previous publication (Zgarbova et al. <i>J. Chem. Theory Comput.</i> <b>2011</b>, <i>7</i>, 2886). The described procedure may help to provide consistently better force field parameters than the currently used parametrization approaches

Mapping the Chemical Space of the RNA Cleavage and Its Implications for Ribozyme Catalysis

Ribozymes utilize diverse catalytic strategies. We report systematic quantum chemical calculations mapping the catalytic space of RNA cleavage by comparing all chemically feasible reaction mechanisms of RNA self-cleavage, using appropriate model systems including those chemical groups that may directly participate in ribozyme catalysis. We calculated the kinetics of uncatalyzed cleavage reactions proceeding via both monoanionic and dianionic pathways, and explicitly probed effects of various groups acting as general bases (GBs) and/or general acids (GAs), or electrostatic transition state stabilizers. In total, we explored 115 different mechanisms. The dianionic scenarios are generally preferred to monoanionic scenarios, although they may compete with one-another under some conditions. Direct GA catalysis seems to exert the dominant catalytic effect, while GB catalysis and electrostatic stabilization are less efficient. Our results indirectly suggest that the dominant part of the catalytic effect might be explained by the shift of the reaction mechanism from the mechanism of uncatalyzed cleavage to the mechanism occurring in ribozymes. This would contrast typical protein enzymes, primarily achieving catalysis by overall electrostatic effects in their catalytic center

Quantum Monte Carlo Methods Describe Noncovalent Interactions with Subchemical Accuracy

An accurate description of noncovalent interaction energies is one of the most challenging tasks in computational chemistry. To date, nonempirical CCSD­(T)/CBS has been used as a benchmark reference. However, its practical use is limited due to the rapid growth of its computational cost with the system complexity. Here, we show that the fixed-node diffusion Monte Carlo (FN-DMC) method with a more favorable scaling is capable of reaching the CCSD­(T)/CBS within subchemical accuracy (<0.1 kcal/mol) on a testing set of six small noncovalent complexes including the water dimer. In benzene/water, benzene/methane, and the T-shape benzene dimer, FN-DMC provides interaction energies that agree within 0.25 kcal/mol with the best available CCSD­(T)/CBS estimates. The demonstrated predictive power of FN-DMC therefore provides new opportunities for studies of the vast and important class of medium/large noncovalent complexes

Adsorption of Small Organic Molecules on Graphene

We present a combined experimental and theoretical quantification of the adsorption enthalpies of seven organic molecules (acetone, acetonitrile, dichloromethane, ethanol, ethyl acetate, hexane, and toluene) on graphene. Adsorption enthalpies were measured by inverse gas chromatography and ranged from −5.9 kcal/mol for dichloromethane to −13.5 kcal/mol for toluene. The strength of interaction between graphene and the organic molecules was estimated by density functional theory (PBE, B97D, M06-2X, and optB88-vdW), wave function theory (MP2, SCS­(MI)-MP2, MP2.5, MP2.X, and CCSD­(T)), and empirical calculations (OPLS-AA) using two graphene models: coronene and infinite graphene. Symmetry-adapted perturbation theory calculations indicated that the interactions were governed by London dispersive forces (amounting to ∼60% of attractive interactions), even for the polar molecules. The results also showed that the adsorption enthalpies were largely controlled by the interaction energy. Adsorption enthalpies obtained from <i>ab initio</i> molecular dynamics employing non-local optB88-vdW functional were in excellent agreement with the experimental data, indicating that the functional can cover physical phenomena behind adsorption of organic molecules on graphene sufficiently well

Energies and 2′-Hydroxyl Group Orientations of RNA Backbone Conformations. Benchmark CCSD(T)/CBS Database, Electronic Analysis, and Assessment of DFT Methods and MD Simulations

Sugar–phosphate backbone is an electronically complex molecular segment imparting RNA molecules high flexibility and architectonic heterogeneity necessary for their biological functions. The structural variability of RNA molecules is amplified by the presence of the 2′-hydroxyl group, capable of forming multitude of intra- and intermolecular interactions. Bioinformatics studies based on X-ray structure database revealed that RNA backbone samples at least 46 substates known as rotameric families. The present study provides a comprehensive analysis of RNA backbone conformational preferences and 2′-hydroxyl group orientations. First, we create a benchmark database of estimated CCSD­(T)/CBS relative energies of all rotameric families and test performance of dispersion-corrected DFT-D3 methods and molecular mechanics in vacuum and in continuum solvent. The performance of the DFT-D3 methods is in general quite satisfactory. The B-LYP-D3 method provides the best trade-off between accuracy and computational demands. B3-LYP-D3 slightly outperforms the new PW6B95-D3 and MPW1B95-D3 and is the second most accurate density functional of the study. The best agreement with CCSD­(T)/CBS is provided by DSD-B-LYP-D3 double-hybrid functional, although its large-scale applications may be limited by high computational costs. Molecular mechanics does not reproduce the fine energy differences between the RNA backbone substates. We also demonstrate that the differences in the magnitude of the hyperconjugation effect do not correlate with the energy ranking of the backbone conformations. Further, we investigated the 2′-hydroxyl group orientation preferences. For all families, we conducted a QM and MM hydroxyl group rigid scan in gas phase and solvent. We then carried out set of explicit solvent MD simulations of folded RNAs and analyze 2′-hydroxyl group orientations of different backbone families in MD. The solvent energy profiles determined primarily by the sugar pucker match well with the distribution data derived from the simulations. The QM and MM energy profiles predict the same 2′-hydroxyl group orientation preferences. Finally, we demonstrate that the high energy of unfavorable and rarely sampled 2′-hydroxyl group orientations can be attributed to clashes between occupied orbitals

Noncanonical α/γ Backbone Conformations in RNA and the Accuracy of Their Description by the AMBER Force Field

The sugar–phosphate backbone of RNA can exist in diverse rotameric substates, giving RNA molecules enormous conformational variability. The most frequent noncanonical backbone conformation in RNA is α/γ = t/t, which is derived from the canonical backbone by a crankshaft motion and largely preserves the standard geometry of the RNA duplex. A similar conformation also exists in DNA, where it has been extensively studied and shown to be involved in DNA–protein interactions. However, the function of the α/γ = t/t conformation in RNA is poorly understood. Here, we present molecular dynamics simulations of several prototypical RNA structures obtained from X-ray and NMR experiments, including canonical and mismatched RNA duplexes, UUCG and GAGA tetraloops, Loop E, the sarcin–ricin loop, a parallel guanine quadruplex, and a viral pseudoknot. The stability of various noncanonical α/γ backbone conformations was analyzed with two AMBER force fields, ff99bsc0χ_OL3 and ff99bsc0χ_OL3 with the recent εζ_OL1 and β_OL1 corrections for DNA. Although some α/γ substates were stable with seemingly well-described equilibria, many were unstable in our simulations. Notably, the most frequent noncanonical conformer α/γ = t/t was unstable in both tested force fields. Possible reasons for this instability are discussed. Our work reveals a potentially important artifact in RNA force fields and highlights a need for further force field refinement

Energies and 2′-Hydroxyl Group Orientations of RNA Backbone Conformations. Benchmark CCSD(T)/CBS Database, Electronic Analysis, and Assessment of DFT Methods and MD Simulations

Sugar–phosphate backbone is an electronically complex molecular segment imparting RNA molecules high flexibility and architectonic heterogeneity necessary for their biological functions. The structural variability of RNA molecules is amplified by the presence of the 2′-hydroxyl group, capable of forming multitude of intra- and intermolecular interactions. Bioinformatics studies based on X-ray structure database revealed that RNA backbone samples at least 46 substates known as rotameric families. The present study provides a comprehensive analysis of RNA backbone conformational preferences and 2′-hydroxyl group orientations. First, we create a benchmark database of estimated CCSD­(T)/CBS relative energies of all rotameric families and test performance of dispersion-corrected DFT-D3 methods and molecular mechanics in vacuum and in continuum solvent. The performance of the DFT-D3 methods is in general quite satisfactory. The B-LYP-D3 method provides the best trade-off between accuracy and computational demands. B3-LYP-D3 slightly outperforms the new PW6B95-D3 and MPW1B95-D3 and is the second most accurate density functional of the study. The best agreement with CCSD­(T)/CBS is provided by DSD-B-LYP-D3 double-hybrid functional, although its large-scale applications may be limited by high computational costs. Molecular mechanics does not reproduce the fine energy differences between the RNA backbone substates. We also demonstrate that the differences in the magnitude of the hyperconjugation effect do not correlate with the energy ranking of the backbone conformations. Further, we investigated the 2′-hydroxyl group orientation preferences. For all families, we conducted a QM and MM hydroxyl group rigid scan in gas phase and solvent. We then carried out set of explicit solvent MD simulations of folded RNAs and analyze 2′-hydroxyl group orientations of different backbone families in MD. The solvent energy profiles determined primarily by the sugar pucker match well with the distribution data derived from the simulations. The QM and MM energy profiles predict the same 2′-hydroxyl group orientation preferences. Finally, we demonstrate that the high energy of unfavorable and rarely sampled 2′-hydroxyl group orientations can be attributed to clashes between occupied orbitals