Static and dynamic structure of Pu3+ in molten LiCl-KCl eutectic revealed by first-principles molecular dynamics simulations

The local coordination structure, as well as its structural dynamics, of molten LiCl-KCl-PuCl₃ mixture is revealed by first-principles molecular dynamics (FPMD) simulations in terms of radial distribution functions, partial structural factors, and van Hove correlation functions. The self-diffusion coefficients and ionic conductivities are evaluated from the mean square displacements of ions, and the viscosity is then estimated from the self-diffusion coefficient of Pu³⁺. It is concluded that the FPMD simulations give satisfactory results compared with existing literature values. Therefore, the FPMD simulations can provide basic physicochemical information if such information is unavailable in literature and microscopic insight into the mechanism of the pyroprocessing of spent nuclear fuels.     

Pressure-induced phase transition in wurtzite ZnTe: an ab initio study

A constant pressure ab initio MD technique and density functional theory with a generalized gradient approximation (GGA) was used to study the pressure-induced phase transition in wurtzite ZnTe. A first-order phase transition from the wurtzite structure to a Cmcm structure was successfully observed in a constant-pressure molecular dynamics simulation. This phase transformation was also analyzed using enthalpy calculations. We also investigated the stability of wurtzite (WZ) and zinc-blende (ZB) phases from energy–volume calculations, and found that both structures show quite similar equations of state and transform into a Cmcm structure at 16 GPa using enthalpy calculations, in agreement with experimental observations. The transition phase, lattice parameters and bulk properties we obtained are comparable with experimental and theoretical data.     

Promotion of Crystal Phase Transitions by Mass-of-cell Control in Molecular Dynamics Simulations: Phase Transitions in Benzene Crystals

Abstract

The promotion of crystal phase transitions in molecular dynamics (MD) simulations was realized by controlling the momentum of the MD cell. It was implemented by increasing the mass or velocity of the MD cell instantaneously during simulations within the framework of the constant-pressure method by Parrinello and Rahman. This method induced phase transitions in benzene crystals which have not been obtained in conventional MD simulations. This method is useful for the global search of stable (and metastable) crystal structures.     

Constitutive properties of contacting materials with a finite-sized microstructure

Materials consisting of macro-molecules that are set in a structure and interact via contact interactions are investigated. The analysis is analytical, based on the methodology developed for granular materials by Jenkins J.T. and Koenders M.A. “The incremental response of random aggregates of round particles” European Physics Journal E., 13, 2004 113–123. The stiffness tensor is obtained and the results are screened for auxetic properties. Two-dimensional materials are investigated. For regular packings isotropic and anisotropic structures are examined. It is demonstrated that isotropic materials in this category are never auxetic. Heterogeneous materials are also analysed. It is shown that auxetic behaviour is enhanced when structural variation is present. By contrast, auxetic behaviour is suppressed when constitutive heterogeneity is present. The results of the analysis may be employed to scrutinize numerical simulations.     

The Possible Structural Models for Polyglutamine Aggregation: A Molecular Dynamics Simulations Study

Abstract

Huntington's disease is a neurodegenerative disorder caused by a polyglutamine (polyQ) expansion near the N-terminus of huntingtin. Previous studies have suggested that polyQ aggregation occurs only when the number of glutamine (Q) residues is more than 36-40, the disease threshold. However, the structural characteristics of polyQ nucleation in the very early stage of aggregation still remain elusive. In this study, we designed 18 simulation trials to determine the possible structural models for polyQ nucleation and aggregation with various shapes and sizes of initial β-helical structures, such as left-handed circular, right-handed rectangular, and left- and right-handed triangular. Our results show that the stability of these models significantly increases with increasing the number of rungs, while it is rather insensitive to the number of Qs in each rung. In particular, the 3-rung β-helical models are stable when they adopt the left-handed triangular and right-handed rectangular conformations due to the fact that they preserve high β-turn and β-sheet contents, respectively, during the simulation courses. Thus, we suggested that these two stable β-helical structures with at least 3 rungs might serve as the possible nucleation seeds for polyQ depending on how the structural elements of β-turn and β-sheet are sampled and preserved during the very early stage of aggregation.     

Structural insights into the anti-cancer activity of quercetin on G-tetrad,mixed G-tetrad,and G-quadruplex DNA using quantum chemical and molecular dynamics simulations

Abstract

Human telomerase referred as ‘terminal transferase’ is a nucleoprotein enzyme which inhibits the disintegration of telomere length and act as a drug target for the anticancer therapy. The tandem repeating structure of telomere sequence forms the guanine-rich quadruplex structures that stabilize stacked tetrads. In our present work, we have investigated the interaction of quercetin with DNA tetrads using DFT. Geometrical analysis revealed that the influence of quercetin drug induces the structural changes into the DNA tetrads. Among DNA tetrads, the quercetin stacked with GCGC tetrad has the highest interaction energy of ?88.08?kcal/mol. The binding mode and the structural stability are verified by the absorption spectroscopy method. The longer wavelength was found at 380?nm and it exhibits bathochromic shift. The findings help us to understand the binding nature of quercetin drug with DNA tetrads and it also inhibits the telomerase activity. Further, the quercetin drug interacted with G-quadruplex DNA by using molecular dynamics (MD) simulation studies for 100?ns simulation at different temperatures and different pH levels (T?=?298 K, 320?K and pH = 7.4, 5.4). The structural stability of the quercetin with G-quadruplex structure is confirmed by RMSD. For the acidic condition (pH = 5.4), the binding affinity is higher toward G-quadruplex DNA, this result resembles that the quercetin drug is well interacted with G-quadruplex DNA at acidic condition (pH = 7.4) than the neutral condition. The obtained results show that quercetin drug stabilizes the G-quadruplex DNA, which regulates telomerase enzyme and it potentially acts as a novel anti-cancer agent.

Communicated by Ramaswamy H. Sarma     

Molecular dynamics simulations of a double unit cell in a protein crystal: volume relaxation at constant pressure and correlation of motions between the two unit cells

Eight molecular dynamics simulations of a double crystal unit cell of ubiquitin were performed to investigate the effects of simulating at constant pressure and of simulating two unit cells compared to a single unit cell. To examine the influence of different simulation conditions, the constant-pressure and constant-volume simulations were each performed with and without counterions and using two different treatments of the long-range electrostatic interactions (lattice-sum and reaction-field methods). The constant-pressure simulations were analyzed in terms of unit cell deformation and accompanying protein deformations. Energetic and structural properties of the proteins in the simulations of the double unit cell were compared to the results of previously reported one-unit-cell simulations. Correlation between the two unit cells was also investigated based on relative translational and rotational movements of the proteins and on dipole fluctuations. The box in the constant-pressure simulations is found to deform slowly to reach convergence only after 5-10 ns. This deformation does not result from a distortion in the structure of the proteins but rather from changes in protein packing within the unit cell. The results of the double-unit-cell simulations are closely similar to the results of the single-unit-cell simulations, and little motional correlation is found between the two unit cells.     

The free energy of a liquid when viewed as a population of overlapping clusters

The expression of the free energy of a liquid in terms of an explicit decomposition of the particle configurations into local coordination clusters is examined. We argue that the major contribution to the entropy associated with structural fluctuations arises from the local athermal constraints imposed by the overlap of adjacent coordination shells. In the context of the recently developed Favoured Local Structure model [Soft Matt. 11, 3322 (2015)], we derive explicit expressions for the structural energy and entropy in the high-temperature limit, compare this approximation with simulation data and consider the extension of this free energy to the case of spatial inhomogeneity in the distribution of local structures.     

Structural Transformations of Ice at High Pressures Via Molecular Dynamics Simulations

Abstract

A simple classical model is used for the study of the structural transformations of ice under high pressures, such as ice VIII to VII and X, via classical molecular dynamics (MD) simulation. In the present MD simulation, pair potentials of a simple form between pair of atoms and a thee-body potential representing the H-O-H angle dependence, originally developed by Kawamura et al., were used. Starting with a stable ice VIII at low pressure and low temperature, we have carried out two different MD runs, one with increasing pressure keeping the temperature constant (simulation I) and the other with increasing temperature under constant pressure (simulation II). From these MD simulations we have obtained the structural transformations from ice VIII to VII for both simulations; the former was finally transformed into ice X for the simulation I. The present results are compatible with recent experiments on high pressure ices.     

Molecular Dynamic Simulations of the N-Terminal Receiver Domain of NtrC Reveal Intrinsic Conformational Flexibility in the Inactive State

Abstract

The N-terminal receiver domain of NtrC is the molecular switch in the two-component signal transduction. It is the first protein where structures of both the active (phosphyroylated) and inactive (unphosphyroylated) states are determined experimentally. Phosphorylation of the NtrC at the active site induces large structural change. NMR experiments suggested that the wild type unphosphorylated NtrC adopts both the active and the inactive conformations and the phosphorylation stabilizes the active conformations. We applied free (unconstrained) molecular dynamic (MD) simulation to examine the intrinsic flexibilities and stabilities of the NtrC receiver domain in both the active and inactive conformations. Molecular dynamic simulations showed that the inactive state of NtrC receiver domain is more flexible than the active state. There were large movements in helix 4 and loop β3-α3 which coincide with major structural differences between the inactive and active states. We observed large root-mean-square deviations from the initial starting structure and the large root-mean-square fluctuations during MD simulation for the inactive state. We then investigated the activation pathway with Targeted MD simulation. We show that the intrinsic flexibility in the loop β3-α3 plays an important role in triggering the conformational change. Phosphorylation at the active site may serve to stabilize the conformational change. These results together suggest that the unphosphorylated NtrC receiver domain could be involved in a conformational equilibrium between two different states.     

Regioselectivity in Sonogashira synthesis of 6-(4-nitrobenzyl)-2-phenylthiazolo[3,2-b]1,2,4-triazole: a quantum chemistry study

In the present research, the experimentally observed regioselectivity in Sonogashira synthesis of 6-(4-nitrobenzyl)-2-phenylthiazolo[3,2-b]1,2,4triazole has been modeled by means of density functional theory (DFT) employed to investigate the structural and thermochemical aspects of this synthesis in the gas and solution phases. Comparison of our calculated structural parameters of the title compound with the available X-ray crystallographical data demonstrate a reliable agreement. Then, the effect of two different solvents, DMF and ethanol, are examined via polarized continuum model calculations, showing a significant decrease in the computed values of the reaction enthalpy and free energy changes compared with the gas phase results. We have also considered two tautomeric structures of the intermediate species that it seems the mode of its intermolecular cyclization has an important role in regioselectivity of the final products. Moreover, all obtained results in the gas and solution phases also confirm that the synthesis of the title compound is thermodynamically more favorable than the other regioisomeric product. We also discuss the thermodynamical feasibility of this reaction at higher temperatures. Finally, we concentrate on the survey of substituent effect by choosing electron-withdrawing and electron-donating groups on the aryl iodide. Our calculated thermochemical data in the gas and solution phases indicate that the use of electron-withdrawing moieties is more favorable thermodynamically than electron-donating ones which has been previously concluded via the experimental elucidations.

Theoretical Analysis of the Base Stacking in DNA: Choice of the Force Field and a Comparison with the Oligonucleotide Crystal Structures

Abstract

It follows from previous studies that changes in the base pair vertical separation (BPVS) influence the architecture of DNA much more than any other conformational parameter. This inspired us to compare BPVS in the available oligonucleotide crystal structures with the optimum values provided by nine different empirical potentials employed in the theoretical studies of DNA conformation. This comparison shows that BPVS is reproduced by three fields in all steps of the highly resolved o] i go nucleoli de crystal structures while the remaining six empirical potentials, including AMBER, GROMOS and CHARMM, provide systematic deviations. We further find that the base pairs are poorly stacked (mostly compressed) in some other refined DNA crystal structures. Our analysis indicates that this poor stacking originates from improperly determined positions of the bases. The approach described in the present communication can be used to identify DNA structures which are not accurate enough for studies of the relationships between the base sequence and DNA conformation.     

Ensembler: Enabling High-Throughput Molecular Simulations at the Superfamily Scale

The rapidly expanding body of available genomic and protein structural data provides a rich resource for understanding protein dynamics with biomolecular simulation. While computational infrastructure has grown rapidly, simulations on an omics scale are not yet widespread, primarily because software infrastructure to enable simulations at this scale has not kept pace. It should now be possible to study protein dynamics across entire (super)families, exploiting both available structural biology data and conformational similarities across homologous proteins. Here, we present a new tool for enabling high-throughput simulation in the genomics era. Ensembler takes any set of sequences—from a single sequence to an entire superfamily—and shepherds them through various stages of modeling and refinement to produce simulation-ready structures. This includes comparative modeling to all relevant PDB structures (which may span multiple conformational states of interest), reconstruction of missing loops, addition of missing atoms, culling of nearly identical structures, assignment of appropriate protonation states, solvation in explicit solvent, and refinement and filtering with molecular simulation to ensure stable simulation. The output of this pipeline is an ensemble of structures ready for subsequent molecular simulations using computer clusters, supercomputers, or distributed computing projects like Folding@home. Ensembler thus automates much of the time-consuming process of preparing protein models suitable for simulation, while allowing scalability up to entire superfamilies. A particular advantage of this approach can be found in the construction of kinetic models of conformational dynamics—such as Markov state models (MSMs)—which benefit from a diverse array of initial configurations that span the accessible conformational states to aid sampling. We demonstrate the power of this approach by constructing models for all catalytic domains in the human tyrosine kinase family, using all available kinase catalytic domain structures from any organism as structural templates. Ensembler is free and open source software licensed under the GNU General Public License (GPL) v2. It is compatible with Linux and OS X. The latest release can be installed via the conda package manager, and the latest source can be downloaded from https://github.com/choderalab/ensembler.     

Reproductive biology of the viviparous scorpion,Liocheles australasiae (Fabricius) (Arachnida,Scorpiones, Ischnuridae) III. Structural types and functional phases of the adult ovary

Summary

Five structural types of the adult ovary were distinguished in a parthenogenetic viviparous scorpion Liocheles australasiae based on the presence or absence of swollen ovarian diverticula (SD) containing embryos and/or empty ones (ED) as remnants of past pregnancies. These structural types seem to correspond to the following ovarian functional phases: the ovary (1) with SD and without ED corresponds to the first pregnancy; (2) without SD and with ED to after the first parturition; (3) with SD and ED to the second pregnancy; (4) without SD and with old and new ED to after the second parturition; and (5) with SD and old and new ED to the third pregnancy. Such correspondence indicates that a female can repeat pregnancies at least three times. Some possible cases in which the present structural types correspond to other functional phases were also discussed.     

Molecular dynamics force probe simulations of antibody/antigen unbinding: entropic control and nonadditivity of unbinding forces

Unbinding of a spin-labeled dinitrophenyl (DNP) hapten from the monoclonal antibody AN02 F(ab) fragment has been studied by force probe molecular dynamics (FPMD) simulations. In our nanosecond simulations, unbinding was enforced by pulling the hapten molecule out of the binding pocket. Detailed inspection of the FPMD trajectories revealed a large heterogeneity of enforced unbinding pathways and a correspondingly large flexibility of the binding pocket region, which exhibited induced fit motions. Principal component analyses were used to estimate the resulting entropic contribution of approximately 6 kcal/mol to the AN02/DNP-hapten bond. This large contribution may explain the surprisingly large effect on binding kinetics found for mutation sites that are not directly involved in binding. We propose that such "entropic control" optimizes the binding kinetics of antibodies. Additional FPMD simulations of two point mutants in the light chain, Y33F and I96K, provided further support for a large flexibility of the binding pocket. Unbinding forces were found to be unchanged for these two mutants. Structural analysis of the FPMD simulations suggests that, in contrast to free energies of unbinding, the effect of mutations on unbinding forces is generally nonadditive.     

Shaker pore structure as predicted by annealed atomic simulation using symmetry and novel geometric restraints

Recent studies making use of channel-blocking peptides as molecular calipers have revealed the architecture of the pore-forming region of Shaker-type potassium channels. Here we show that the low-resolution, experimentally derived geometric information can be incorporated as restraints within the context of an annealed molecular dynamics simulation to predict an atomic structure for the channel pore which, by virtue of restraints, conforms to the experimental evidence. The simulation is reminiscent of the computational method employed by nuclear magnetic resonance (NMR) spectroscopists to resolve solution structures of biological macromolecules, but in lieu of restraints conventionally derived from NMR spectra, novel restraints are developed that include side-chain orientation of amino acid residues and assumed symmetry of protein subunits. The method presented here offers the possibility of expanding cooperation between simulation and experiment in developing structural models, especially for systems such as ion channels whose three-dimensional structures may not be amenable to determination by direct methods at the present time.     

Simulation of a Hard-Sphere Fluid in Bicontinuous Random Media

Abstract

The influence of solid-phase connectivity on size-exclusion partitioning and on diffusion of a dilute hard-sphere fluid in overlapping and nonoverlapping spheres models of porous media is investigated using molecular dynamics and Monte Carlo simulation techniques. Four models are examined, two of which are subject to constrained bicontinuity of the pore and solid phases and two in which the solid spheres in the assemblies are randomly distributed in space. It is shown that at moderate to high porosities, connected (bicontinuous) structures lead to a significant increase in the partition and diffusion coefficients when the particles of the pore fluid are of finite size. The consequences of solid phase connectivity are also clearly illustrated in the long-time decay of the velocity autocorrelation function (VACF) of the diffusing particles, particularly in the vicinity of the percolation threshold. Under these conditions the power law exponents on the long-time tail of the VACF are generally found to be higher in connected models than in random systems and the importance of this result is demonstrated using one of the scaling rules of percolation theory. The simulation results are also compared with the predictions of current theories of partitioning and diffusion in random sphere assemblies and, with reference to experimental data available from the literature, it is shown that bicontinuous models are better representations of real porous media.     

Major groove width variations in RNA structures determined by NMR and impact of <Superscript>13</Superscript>C residual chemical shift anisotropy and <Superscript>1</Superscript>H–<Superscript>13</Superscript>C residual dipolar coupling on refinement

Ribonucleic acid structure determination by NMR spectroscopy relies primarily on local structural restraints provided by ¹H– ¹H NOEs and J-couplings. When employed loosely, these restraints are broadly compatible with A- and B-like helical geometries and give rise to calculated structures that are highly sensitive to the force fields employed during refinement. A survey of recently reported NMR structures reveals significant variations in helical parameters, particularly the major groove width. Although helical parameters observed in high-resolution X-ray crystal structures of isolated A-form RNA helices are sensitive to crystal packing effects, variations among the published X-ray structures are significantly smaller than those observed in NMR structures. Here we show that restraints derived from aromatic ¹H– ¹³C residual dipolar couplings (RDCs) and residual chemical shift anisotropies (RCSAs) can overcome NMR restraint and force field deficiencies and afford structures with helical properties similar to those observed in high-resolution X-ray structures.     

Structural alterations by five disease-causing mutations in the low-pH conformation of human dihydrolipoamide dehydrogenase (hLADH) analyzed by molecular dynamics – Implications in functional loss and modulation of reactive oxygen species generation by pathogenic hLADH forms

Human dihydrolipoamide dehydrogenase (hLADH) is a flavoenzyme component (E3) of the human alpha-ketoglutarate dehydrogenase complex (α-KGDHc) and few other dehydrogenase complexes. Pathogenic mutations of hLADH cause severe metabolic diseases (atypical forms of E3 deficiency) that often escalate to cardiological or neurological presentations and even premature death; the pathologies are generally accompanied by lactic acidosis. hLADH presents a distinct conformation under acidosis (pH 5.5–6.8) with lower physiological activity and the capacity of generating reactive oxygen species (ROS). It has been shown by our laboratory that selected pathogenic mutations, besides lowering the physiological activity of hLADH, significantly stimulate ROS generation by hLADH, especially at lower pH, which might play a role in the pathogenesis of E3-deficiency in respective cases. Previously, we generated by molecular dynamics (MD) simulation the low-pH hLADH structure and analyzed the structural changes induced in this structure by eight of the pathogenic mutations of hLADH. In the absence of high resolution mutant structures these pieces of information are crucial for the mechanistic investigation of the molecular pathogeneses of the hLADH protein. In the present work we analyzed by molecular dynamics simulation the structural changes induced in the low-pH conformation of hLADH by five pathogenic mutations of hLADH; the structures of these disease-causing mutants of hLADH have never been examined before.     

Hydration of krypton and consideration of clathrate models of hydrophobic effects from the perspective of quasi-chemical theory

Ab initio molecular dynamics (AIMD) results on a krypton-water liquid solution are presented and compared to recent XAFS results for the radial hydration structure for a Kr atom in liquid water solution. Though these AIMD calculations have important limitations of scale, the comparisons with the liquid solution results are satisfactory and significantly different from the radial distributions extracted from the data on the solid Kr/H(2)O clathrate hydrate phase. The calculations also produce the coordination number distribution that can be examined for metastable coordination structures suggesting possibilities for clathrate-like organization; none are seen in these results. Clathrate pictures of hydrophobic hydration are discussed, as is the quasi-chemical theory that should provide a basis for clathrate pictures. Outer shell contributions are discussed and estimated; they are positive and larger than the positive experimental hydration free energy of Kr(aq), implying that inner shell contributions must be negative and of comparable size. Clathrate-like inner shell hydration structures on a Kr atom solute are obtained for some, but not all, of the coordination number cases observed in the simulation. The structures found have a delicate stability. Inner shell coordination structures extracted from the simulation of the liquid, and then subjected to quantum chemical optimization, always decomposed. Interactions with the outer shell material are decisive in stabilizing coordination structures observed in liquid solution and in clathrate phases. The primitive quasi-chemical estimate that uses a dielectric model for the influence of the outer shell material on the inner shell equilibria gives a contribution to hydration free energy that is positive and larger than the experimental hydration free energy. The 'what are we to tell students' question about hydrophobic hydration, often answered with structural clathrate pictures, is then considered; we propose an alternative answer that is consistent with successful molecular theories of hydrophobic effects and based upon distinctive observable properties of liquid water. Considerations of parsimony, for instance Ockham's razor, then suggest that additional structural hypotheses in response to 'what are we to tell students' are not required at this stage.