Modeling the Tertiary Structure of the Rift Valley Fever Virus L Protein.

A tertiary structure governs, to a great extent, the biological activity of a protein in the living cell and is consequently a central focus of numerous studies aiming to shed light on cellular processes central to human health. Here, we aim to elucidate the structure of the Rift Valley fever virus (RVFV) L protein using a combination of in silico techniques. Due to its large size and multiple domains, elucidation of the tertiary structure of the L protein has so far challenged both dry and wet laboratories. In this work, we leverage complementary perspectives and tools from the computational-molecular-biology and bioinformatics domains for constructing, refining, and evaluating several atomistic structural models of the L protein that are physically realistic. All computed models have very flexible termini of about 200 amino acids each, and a high proportion of helical regions. Properties such as potential energy, radius of gyration, hydrodynamics radius, flexibility coefficient, and solvent-accessible surface are reported. Structural characterization of the L protein enables our laboratories to better understand viral replication and transcription via further studies of L protein-mediated protein-protein interactions. While results presented a focus on the RVFV L protein, the following workflow is a more general modeling protocol for discovering the tertiary structure of multidomain proteins consisting of thousands of amino acids.

Density functional theory study of neutral and oxidized thiophene oligomers.

The effect of oxidation on the energetics and structure of thiophene (Th) oligomers is studied with density functional theory at the B3PW91∕6-311++G(d,p) level. Neutral n-Th oligomers (2 < n < 13) are gently curved planar chains. Ionization potential and electron affinity results show that n-Th oligomers are easier to be oxidized as their chain length increases. Oxidation states +2, +4, +6, and +8 are energetically stable in 12-Th. Upon oxidation the conjugated backbone of 12-Th switches from extended benzenoid phase to quinoid phase localized on groups of monomers regularly spaced along the chain. Oxidized states +2, +4, +6, and +8 of 12-Th display two +1e localized at the ends of their chains only because of the finite size of the chains. In 12-Th this end-effect extends over the two terminal monomers forming a positive-negative charge duet. This peculiar charge localization makes n-Th oligomers different from other conducting polymers with similar structure, such as polypyrrole. The spectrum of single-electron molecular states of oxidized 12-Th displays two localized single-electron states in the HOMO-LUMO energy gap per +2 oxidation state. Oligothiophene 12-Th doped with F atoms at 1:2 concentration presents a charge transfer of 3.4 e from oligomer to dopants that increases to 4.8 e in the presence of solvent. The charge distribution in these F-doped oligomers is similar to the +4 oxidation state of 12-Th. It is predicted that dopants produce an enhanced charge transfer localized in the proximity of their locations enhancing the formation of bipolarons in the central part of the oligomer chain.

Distinctive Formation of PEG-Lipid Nanopatches onto Solid Polymer Surfaces Interfacing Solvents from Atomistic Simulation.

The interface between solid poly(lactic acid-co-glycolic acid), PLGA, and solvents is described by large-scale atomistic simulations for water, ethyl acetate, and the mixture of them at ambient conditions. Interactions at the interface are dominated by Coulomb forces for water and become overwhelmingly dispersive for the other two solvents. This effect drives a neat liquid-phase separation of the mixed solvent, with ethyl acetate covering the PLGA surface and water being segregated away from it. We explore with all-atom Molecular Dynamics the formation of macromolecular assemblies on the surface of the PLGA-solvent interface when DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(polyethylene glycol)n amine, is added to the solvent. By following in time the deposition of the DSPE-PEG macromolecules onto the PLGA surface, the mechanism of how nanopatches remain adsorbed to the surface despite the presence of the solvent is probed. These patches have a droplet-like aspect when formed at the PLGA-water interface that flatten in the PLGA-ethyl acetate interface case. Dispersive forces are dominant for the nanopatch adhesion to the surface, while electrostatic forces are dominant for keeping the solvent around the new formations. Considering the droplet-like patches as wetting the PLGA surface, we predict an effective wetting behavior at the water interface that fades significantly at the ethyl acetate interface. The predicted mechanism of PEG-lipid nanopatch formation may be generally applicable for tailoring the synthesis of asymmetric PLGA nanoparticles for specific drug delivery conditions.

Forecasting molecular dynamics energetics of polymers in solution from supervised machine learning.

Machine learning techniques including neural networks are popular tools for chemical, physical and materials applications searching for viable alternative methods in the analysis of structure and energetics of systems ranging from crystals to biomolecules. Efforts are less abundant for prediction of kinetics and dynamics. Here we explore the ability of three well established recurrent neural network architectures for reproducing and forecasting the energetics of a liquid solution of ethyl acetate containing a macromolecular polymer-lipid aggregate at ambient conditions. Data models from three recurrent neural networks, ERNN, LSTM and GRU, are trained and tested on half million points time series of the macromolecular aggregate potential energy and its interaction energy with the solvent obtained from molecular dynamics simulations. Our exhaustive analyses convey that the recurrent neural network architectures investigated generate data models that reproduce excellently the time series although their capability of yielding short or long term energetics forecasts with expected statistical distributions of the time points is limited. We propose an in silico protocol by extracting time patterns of the original series and utilizing these patterns to create an ensemble of artificial network models trained on an ensemble of time series seeded by the additional time patters. The energetics forecast improve, predicting a band of forecasted time series with a spread of values consistent with the molecular dynamics energy fluctuations span. Although the distribution of points from the band of energy forecasts is not optimal, the proposed in silico protocol provides useful estimates of the solvated macromolecular aggregate fate. Given the growing application of artificial networks in materials design, the data-based protocol presented here expands the realm of science areas where supervised machine learning serves as a decision making tool aiding the simulation practitioner to assess when long simulations are worth to be continued.

Modeling oxidised polypyrrole in the condensed phase with a novel force field.

A novel model potential is developed for simulating oxidised oligopyrroles in condensed phases. The force field is a coarse grained model that represents the pyrrole monomers as planar rigid bodies with fixed charge and dipole moment and the chlorine dopants as point atomic charges. The analytic function contains 17 adjustable parameters that are initially fitted on a database of small structures calculated within all-electron density functional theory. A subsequent potential function refinement is pursued with a battery of condensed phase isothermal-isobaric Metropolis Monte Carlo in-silico simulations at ambient conditions with the goal of implementing a hybrid parametrization protocol enabling agreement with experimentally known thermodynamic properties of oxidised polypyrrole. The condensed system is composed of oligomers containing 12 monomers with a 1:3 dopant-to-monomer concentration. The final set of force field optimised parameters yields an equilibrium density of the condensed system at ambient conditions in excellent agreement with oxidised polypyrrole samples synthesised in wet-laboratories.

Theoretical investigation of the photophysics of methyl salicylate isomers.

The photophysics of methyl salicylate (MS) isomers has been studied using time-dependent density functional theory and large basis sets. First electronic singlet and triplet excited states energies, structure, and vibrational analysis were calculated for the ketoB, enol, and ketoA isomers. It is demonstrated that the photochemical pathway involving excited state intramolecular proton transfer (ESIPT) from the ketoB to the enol tautomer agrees well with the dual fluorescence in near-UV (from ketoB) and blue (from enol) wavelengths obtained from experiments. Our calculation confirms the existence of a double minimum in the excited state pathway along the O-H-O coordinate corresponding to two preferred energy regions: (1) the hydrogen belongs to the OH moiety and the structure of methyl salicylate is ketoB; (2) the hydrogen flips to the closest carboxyl entailing electronic rearrangement and tautomerization to the enol structure. This double well in the excited state is highly asymmetric. The Franck-Condon vibrational overlap is calculated and accounts for the broadening of the two bands. It is suggested that forward and backward ESIPT through the barrier separating the two minima is temperature-dependent and affects the intensity of the fluorescence as seen in experiments. When the enol fluoresces and returns to its ground state, a barrier-less back proton transfer repopulates the ground state of methyl salicylate ketoB. It is also demonstrated that the rotamer ketoA is not stable in an excited state close to the desired emission wavelength. This observation eliminates the conjecture that the near-UV emission of the dual fluorescence originates from the ketoA rotamer. New experimental results for pure MS in the liquid state are reported and theoretical results compared to them.

Solutions and Condensed Phases of PEG2000 from All-Atom Molecular Dynamics.

Extensive all-atom molecular dynamics studies of polyethylene glycol (PEG2000) when solvated and in the polymer bulk condensed phases were performed across a wide temperature range. We proposed two modified all-atom force field and observed the fate of the PEG2000 macromolecule when solvated in water, water with 4% ethanol, and ethyl acetate. In aqueous solutions, the macromolecule collapsed into a prolate spheroidal ball-like structure while adopting a rather elongated coiled structure in ethyl acetate. Inspection of the polymer-condensed phases across the 150-340 K temperature range enabled the atomistic view of the solid glass below the glass transition temperature of 230 K < Tg < 250 K and the rubber behavior above Tg. Predicted properties include the enthalpy, density, and cohesive energy temperature behavior, the specific heat, thermal expansivity, thermal compressibility, bulk modulus, and Hildebrand solubility parameter both below and above Tg. Within the polymer matrix, the PEG2000 macromolecules were entangled displaying a wide distribution of sizes that persisted when transitioning from the glass to the rubbery phases. Calculated properties agree very well with experiments when available or stand as crucial predictions while awaiting experimental measurement. Understanding the thermodynamics and structure of this useful polymer enables the efficient prediction of its behavior when building novel composite materials for nanomedicine and nanotherapeutics.

Monte Carlo study of oligopyrroles in condensed phases.

A classical model potential to simulate pyrrole oligomers in condensed phases is developed in this work. The new potential contains ten parameters that are optimized on a database of energy points calculated within the density functional theory approach. Based on this potential the condensed phase of systems composed of pyrrole oligomers with 4 and 12 monomers is studied as a function of system density. The binding energy, end-to-end distance, radius of gyration, vector and orientational order parameters, and pair correlation functions are reported at T=300 K. The mechanical equilibrium density is determined for both systems. The bulk modulus is reported at these densities, showing that systems composed of short oligomers are softer than systems containing longer oligomers. Analysis of pair correlation functions and order parameters indicates that at equilibrium the system of short oligomers has characteristics of a liquid while the system of longer oligomers shows a chain stacking trend.

Energetics and vibrational analysis of methyl salicylate isomers.

Energetics and vibrational analysis study of six isomers of methyl salicylate in their singlet ground state and first excited triple state is put forward in this work at the density functional theory level and large basis sets. The ketoB isomer is the lowest energy isomer, followed by its rotamer ketoA. For both ketoB and ketoA their enolized tautomers are found to be stable as well as their open forms that lack the internal hydrogen bond. The calculated vibrational spectra are in excellent agreement with IR experiments of methyl salicylate in the vapor phase. It is demonstrated that solvent effects have a weak influence on the stability of these isomers. The ionization reaction from ketoB to ketoA shows a high barrier of 0.67 eV ensuring that thermal and chemical equilibria yield systems containing mostly the ketoB isomer at normal conditions.

Silicon carbide nanostructures: a tight binding approach.

A tight-binding model Hamiltonian is newly parametrized for silicon carbide based on fits to a database of energy points calculated within the density functional theory approach of the electronic energy surfaces of nanoclusters and the total energy of bulk 3C and 2H polytypes at different densities. This TB model includes s and p angular momentum symmetries with nonorthogonal atomic basis functions. With the aid of the new TB model, minima of silicon carbide cagelike clusters, nanotubes, ring-shaped ribbons, and nanowires are predicted. Energetics, structure, growth sequences, and stability patterns are reported for the nanoclusters and nanotubes. The band structure of SiC nanotubes and nanowires indicates that the band gap of the nanotubes ranges from 0.57 to 2.38 eV depending on the chirality, demonstrating that these nanotubes are semiconductors or insulators. One type of nanowire is metallic, another type is semiconductor, and the rest are insulators.

Exploring with Molecular Dynamics the Structural Fate of PLGA Oligomers in Various Solvents.

This study focuses on the solvent effects that promote preferred solvated structures of polylactic-co-glycolic acid (PLGA) oligomers of molecular weight 278, 668, and 1449 u in ethyl acetate, water, and a mixture of both solvents. Our methodology consists of all-atom, explicit solvent molecular dynamics simulations for inspection of the solvated oligomer structures at ambient conditions. Parameters for the generalized Amber force field are developed in this work for the ethyl acetate liquid and the PLGA oligomers. Energetics, oligomer radius of gyration, end-to-end distance, orientational order parameter, flexibility coefficient, and backbone dihedral angles are reported along with a size scaling property yielding a power law for PLGA oligomers in each of the three solvents considered. It is found that the PLGA oligomer has two characteristic states identified by a set of extended structures and a set of collapsed structures, the former being energetically preferred in ethyl acetate and its mixture with water. The two types of PLGA structures occur in the three solvents and although they flip from one to the other in a sporadic fashion, in ethyl acetate, the extended structures may persist for more than 20 ns. The collapsed structures are significantly more frequent in water, occurring seldom in the mixed ethyl acetate-water solvent. PLGA is a biodegradable polymer approved for use in pharmaceutical and biomedical applications. Insights provided therein are of importance for the polymer aggregation process and its glassy state in condensed phases.

Simulating the NaK Eutectic Alloy with Monte Carlo and Machine Learning.

Combining atomistic simulations and machine learning techniques can expedite significantly the materials discovery process. We present an application of such methodological combination for the prediction of the melting transition and amorphous-solid behavior of the NaK alloy at the eutectic concentration. We show that efficient prediction of these properties is possible via machine learning methods trained on the topological local structural properties. The configurations resulting from Monte Carlo annealing of the NaK eutectic alloy are analyzed with topological attributes based on the Voronoi tessellation and using expectation-maximization clustering and Random Forest classification. We show that the Voronoi topological fingerprints make an accurate and fast prediction of the alloy thermal behavior by cataloguing the atomic configurations into three distinct phases: liquid, amorphous solid, and crystalline solid. Melting is found at 230 K by the sharp split of configurations classified as crystalline solid and as liquid. With the proposed metrics, an arrest-motion temperature is identified at 130-140 K through a top down clustering of the atomic configurations catalogued as amorphous solid. This statistical learning paradigm is not restricted to eutectic alloys or thermodynamics, extends the utility of topological attributes in a significant way, and harnesses the discovery of new material properties.

Energetics, structure, and electron detachment spectra of calcium and zinc neutral and anion clusters: a density functional theory study.

A hybrid density functional approach with very large basis sets was used for studying Ca2 through Ca19 and Zn3 through Zn11 neutral clusters and their cluster anions. Energetics, structure, and vibrational analysis of all these neutral clusters and cluster anions are reported. The calculated electron affinities are in excellent agreement with experiment displaying a characteristic kink at Ca10 and Zn10. This kink occurs because the 10-atom neutral cluster is very stable whereas the cluster anion is not. Additionally, the electron detachment binding energies (BEs) up to Ca6(-) and Zn6(-) were identified by analyzing the ground and excited states of the cluster anions and of their corresponding size neutral clusters. The theoretical BE is in very good agreement with experiment for both calcium and zinc cluster anions. The three main peaks in the spectrum correspond to BEs from the ground state of the cluster anion (doublet) to the ground state of the neutral cluster (singlet) and to the first triplet and quintet excited states of the neutral cluster. The calculated energy gap from the lowest BE peak to the second peak is in excellent agreement with experiment. The calculation reproduces very well the energy gap observed in Ca4(-) and Zn4(-), which is larger than those for other sizes and is indicative of the strong stability of the anion and neutral tetramers.

Energetics, structure, and charge distribution of reduced and oxidized n-pyrrole oligomers: a density functional approach.

Polypyrrole is a conjugated polymer prototype of conducting polymers. The energetically preferred spatial conformation of n-pyrrole oligomers (n=1-24) in both the reduced and oxidized phases is obtained and analyzed in this paper within the hybrid density functional theory. Binding energies, gap energies, radius of gyration, end-to-end distance, and vibrational frequencies are reported as functions of oligomer length. Reduced n-pyrrole are bent chains for all sizes showing a dramatic departure from planarity. Vibrational spectra of n-pyrrole oligomers indicate the presence of two fairly size-insensitive frequency regions, which increase in intensity with increasing oligomer size. Several oxidation levels were analyzed for n-pyrrole through the distribution of the carbon-carbon bond orders and single/double bond lengths. It is shown that the oxidation level is directly related to the way positive charge localizes along the n-pyrrole oligomer chain. If charge/n<13, the oligomers are bent and charge is delocalized; if charge/n>/=13, the oligomers are planar and charge notoriously localizes in n/charge regions along the backbone. Calculations with electronegative dopants show that charge localizes in the neighborhood of the dopant. It is demonstrated that one localized state in the gap between the highest occupied and lowest-unoccupied states appears for every +2e in the oxidation level. The band structure of infinite reduced polypyrrole gives a band gap energy in excellent agreement with experiment. The evolution of the band gap and the charge-localized band as a function of polypyrrole oxidation level is reported.

Failure of logarithmic oscillators to serve as a thermostat for small atomic clusters.

A logarithmic oscillator has the outstanding property that the expectation value of its kinetic energy is constant for all stationary states. Recently the ansatz that this property can be used to define a Hamiltonian thermostat has been put forward and a suggestion has been made that this logarithmic oscillator weakly coupled to a small system would serve as a thermostat as long as few degrees of freedom are involved as is the case in atomic clusters. We have applied these ideas to a cluster of four Lennard-Jones atoms and inspected two different models of coupling between the cluster and the logarithmic oscillator in three dimensions. In both cases we show that there is a clear generation of kinetic motion of the cluster center of mass, but that kinetic energy due to interatomic vibrations is not significantly affected by coupling to the logarithmic oscillator. This is a failure of the published ansatz, as the logarithmic oscillator is unable to modify the kinetic energy due to vibrations in small atomic clusters.