Molecular Dynamics Simulation Model Research Articles

Experimental, Thermodynamic, and Molecular Modeling Evaluation of Amorphous Simvastatin-Poly(vinylpyrrolidone) Solid Dispersions.

A crucial step for the selection of proper amorphous solid dispersion (ASD) matrix carriers is the in-depth assessment of drug/polymer physicochemical properties. In this context, the present study extends the work of previously published attempts by evaluating the formation of simvastatin (SIM)-poly(vinylpyrrolidone) (PVP) ASDs with the aid of thermodynamic and molecular modeling. Specifically, the implementation of both Flory-Huggins lattice theory and molecular dynamics (MD) simulations was able to predict the miscibility between the two components (a finding that was experimentally verified via differential scanning calorimetry (DSC) and hot stage polarized microscopy), while a complete temperature-concentration phase-transition profile was constructed, leading to the identification of the thermodynamically metastable and unstable ASD zones. Furthermore, as in the case of previously published reports, the analysis of the ASDs via Fourier transform infrared spectroscopy did not clarify the type and extent of observed molecular interactions. Hence, in the present study, a computer-based MD simulation model was developed for the first time in order to gain an insight into the properties of the observed interactions. MD amorphous assemblies of SIM, PVP, and their mixtures were initially developed, and the calculated glass transition temperatures were in close agreement with experimentally obtained results, indicating that the developed models could be considered as realistic representations of the actual systems. Furthermore, molecular interactions evaluation via radial distribution function and radius of gyration analysis revealed that increasing SIM content results in a significant PVP chain shrinkage, which eventually leads to SIM-SIM amorphous intermolecular interactions, leading to the formation of amorphous drug zones. Finally, MD-based results were experimentally verified via DSC.

Molecular dynamics simulation and theoretical study on heat capacities of supercritical H2O/CO2 mixtures

Molecular dynamics (MD) simulations and calculations based on the Peng-Robinson equation of state (PR-EOS) are carried out to compute the heat capacities of pure H2O and CO2 and supercritical H2O/CO2 mixtures. Using NIST data as a reference, it is found that the two methods generally exhibit comparable and acceptable performance in prediction of the heat capacities of the supercritical fluids. However, in near-critical region for pure supercritical H2O and the supercritical H2O/CO2 mixtures at higher mole fractions of H2O, PR-EOS exhibit poor prediction accuracy while MD simulation models achieve much better performance. The radial distribution function (RDF) and hydrogen bond analysis shows that this should contribute to the ability of MD simulations to deal with the effect of hydrogen bonding. This work is helpful for guiding the future investigation of the heat capacity of other working mixtures in thermodynamic systems based on the supercritical water gasification of coal.

Direct interplay between stereochemistry and conformational preferences in aminoacylated oligoribonucleotides.

To address the structural and dynamical consequences of amino-acid attachment at 2′- or 3′-hydroxyls of the terminal ribose in oligoribonucleotides, we have performed an extensive set of molecular dynamics simulations of model aminoacylated RNA trinucleotides. Our simulations suggest that 3′-modified trinucleotides exhibit higher solvent exposure of the aminoacylester bond and may be more susceptible to hydrolysis than their 2′ counterparts. Moreover, we observe an invariant adoption of well-defined collapsed and extended conformations for both stereoisomers. We show that the average conformational preferences of aminoacylated trinucleotides are determined by their nucleotide composition and are fine-tuned by amino-acid attachment. Conversely, solvent exposure of the aminoacylester bond depends on the attachment site, the nature of attached amino acid and the strength of its interactions with the bases. Importantly, aminoacylated CCA trinucleotides display a systematically higher solvent exposure of the aminoacylester bond and a weaker dependence of such exposure on sidechain interactions than other trinucleotides. These features could facilitate hydrolytic release of the amino acid, especially for 3′ attachment, and may have contributed to CCA becoming the universal acceptor triplet in tRNAs. Our results provide novel atomistic details about fundamental aspects of biological translation and furnish clues about its primordial origins.

Modeling and Simulating of High Chromium Alloy Based on Molecular Dynamics.

High chromium alloy is a kind of metal material with high corrosion resistance and high hardness. It is used in the thrust bearing bush of nuclear main pump in a severe environment. Based on the content of elements in high chromium alloy and the manufacturing preparation process of the alloy, a method for constructing the molecular dynamics (MD) model was proposed to study the machinability of the alloy. The MD simulation model of high chromium alloy was established based on alloy structure with the atomic random permutation and two bubble algorithms. Then, according to the actual manufacturing process of the high chromium alloy, a quenching process was introduced to simulate the actual manufacturing process of the high chromium alloy, so the property of the high chromium alloy model was improved and it was more suitable for precision machining. The accuracy of the model was verified by the internal structure and by calculating the nanohardness and density of the high chromium alloy model after adequate relaxation to studying the nanomachining performance. The coordination number of the high chromium alloy is about 4.3 calculated by integrating the radial distribution function. And there is not a perfect crystal structure in the alloy model. The density of the alloy model is about 7.549 g/cm₂, which agreed with the results of actual experimental measurement. A series of MD simulations were performed to investigate the nanomechanical property of the high chromium alloy by using the MD model. The maximum depth of 2 nm, 2.5 nm and 3 nm indentation simulations were carried out with 3 nm indenter. The results showed that the nanohardness is about 6.951 GPa-8.095 GPa, these properties are very close to the real measured results. The material and the deformation property of the high chromium alloy were stable during the indentation process.

Tailoring the thermal conductivity of Poly(dimethylsiloxane)/Hexagonal boron nitride composite

Molecular dynamics (MD) simulation was employed to predict the thermal conductivity of poly(dimethylsiloxane) (PDMS)/hexagonal boron (h-BN) composite. Two MD simulation models were constructed. Model one is h-BN monolayer being adsorbed by PDMS chains, which is designed to examine the influence mechanism of polymer molecules on the heat conduction of h-BN. The polymer molecules were divided into several layers along the normal direction of the h-BN, which had different impacts on the thermal conductivity of h-BN. Model two is PDMS composites with different volume fractions of h-BN monolayer, which is used to investigate the influence of h-BN on thermal conductivity of the composites. Meanwhile, the orientation of the h-BN under the oscillatory shear was also considered. It presents three regimes on the thermal conductivity increased with the packing fraction after shearing. In general, this work opens some insightful avenues for manipulating the thermal conductivity of PDMS/h-BN composite.

Tropomyosin Cable Formation and Its Influence on the Structural Dynamics of Tropomyosin

Head-to-tail association of coiled-coil tropomyosin dimers produce four-helix bundle “overlapping domains” connecting the dimers together. This polymerization process yields elongated super-helical cables that interact continuously with the surface of the actin filament. While considerable computationally generated information is available on the local and global interactions between isolated (unpolymerized) tropomyosin dimers and F-actin (Li et al., 2011), little is known about the influence of the overlapping domain on the structural-mechanics of tropomyosin and hence corresponding tropomyosin behavior on actin filaments. In an effort to elucidate localized overlapping domain - actin interaction and ensuing regulatory translocation across actin, we compared molecular dynamics simulations of models of single dimeric tropomyosin molecules (as in Li et al., 2010) with new models of tropomyosin cables. The simulations of tropomyosin cables were performed with the tropomyosin polymer constrained to a native super-helical configuration as if linked to a ghost F-actin filament at a radius of 39 Å, thereby maximizing native flexural and twisting motions without being dampened by interaction with F-actin. We have recently shown that torsional motions and sequence-dependent twisting of tropomyosin is initiated and propagated from aspartate-137 and surrounding amino acids and is critical for tropomyosin function (Lehman et al., 2018). We now have shown that the sequence-specific twisting pattern of tropomyosin is virtually unaffected by the additional presence of the overlapping domain, while the flexural motions of tropomyosin are dampened as expected. In addition, related MD shows that torsional (and flexural) mobility of the overlapping domain itself appears to be unaffected by the presence of the remainder of the molecule. We conclude that the material properties of tropomyosin are dominated by its dimeric coiled-coil region and that the main function of overlapping domain is to sponsor tropomyosin polymerization and cable formation.

Phase-change switching in 2D via soft interactions.

We present a new type of phase-change behavior relevant for information storage applications, that can be observed in 2D systems with cluster-forming ability. The temperature-based control of the ordering in 2D particle systems depends on the existence of a crystal-to-glass transition. We perform molecular dynamics simulations of models with soft interactions, demonstrating that the crystalline and amorphous structures can be easily tuned by heat pulses. The physical mechanism responsible for this behavior is a self-assembled polydispersity, that depends on the cluster-forming ability of the interactions. Therefore, the range of real materials that can perform such a transition is very wide in nature, ranging from colloidal suspensions to vortex matter. The state of the art in soft matter experimental setups, controlling interactions, polydispersity and dimensionality, makes it a very fertile ground for practical applications.

Bayesian calibration of force-fields from experimental data: TIP4P water.

Molecular dynamics (MD) simulations give access to equilibrium structures and dynamic properties given an ergodic sampling and an accurate force-field. The force-field parameters are calibrated to reproduce properties measured by experiments or simulations. The main contribution of this paper is an approximate Bayesian framework for the calibration and uncertainty quantification of the force-field parameters, without assuming parameter uncertainty to be Gaussian. To this aim, since the likelihood function of the MD simulation models is intractable in the absence of Gaussianity assumption, we use a likelihood-free inference scheme known as approximate Bayesian computation (ABC) and propose an adaptive population Monte Carlo ABC algorithm, which is illustrated to converge faster and scales better than the previously used ABCsubsim algorithm for the calibration of the force-field of a helium system. The second contribution is the adaptation of ABC algorithms for High Performance Computing to MD simulations within the Python ecosystem ABCpy. This adaptation includes a novel use of a dynamic allocation scheme for Message Passing Interface (MPI). We illustrate the performance of the developed methodology to learn posterior distribution and Bayesian estimates of Lennard-Jones force-field parameters of helium and the TIP4P system of water implemented for both simulated and experimental datasets collected using neutron and X-ray diffraction. For simulated data, the Bayesian estimate is in close agreement with the true parameter value used to generate the dataset. For experimental as well as for simulated data, the Bayesian posterior distribution shows a strong correlation pattern between the force-field parameters. Providing an estimate of the entire posterior distribution, our methodology also allows us to perform the uncertainty quantification of model prediction. This research opens up the possibility to rigorously calibrate force-fields from available experimental datasets of any structural and dynamic property.

Direct Prediction of EPR Spectra from Lipid Bilayers: Understanding Structure and Dynamics in Biological Membranes.

Of the many biophysical techniques now being brought to bear on studies of membranes, electron paramagnetic resonance (EPR) of nitroxide spin probes was the first to provide information about both mobility and ordering in lipid membranes. Here, we report the first prediction of variable temperature EPR spectra of model lipid bilayers in the presence and absence of cholesterol from the results of large scale fully atomistic molecular dynamics (MD) simulations. Three types of structurally different spin probes were employed in order to study different parts of the bilayer. Our results demonstrate very good agreement with experiment and thus confirm the accuracy of the latest lipid force fields. The atomic resolution of the simulations allows the interpretation of the molecular motions and interactions in terms of their impact on the sensitive EPR line shapes. Direct versus indirect effects of cholesterol on the dynamics of spin probes are analysed. Given the complexity of structural organisation in lipid bilayers, the advantage of using a combined MD‐EPR simulation approach is two‐fold. Firstly, prediction of EPR line shapes directly from MD trajectories of actual phospholipid structures allows unambiguous interpretation of EPR spectra of biological membranes in terms of complex motions. Secondly, such an approach provides an ultimate test bed for the up‐to‐date MD simulation models employed in the studies of biological membranes, an area that currently attracts great attention.

It Is Complicated: Curvature, Diffusion, and Lipid Sorting within the Two Membranes of Escherichia coli.

The cell envelope of Gram-negative bacteria is composed of two membranes separated by a soluble region. Here, we report microsecond time scale coarse-grained molecular dynamics simulations of models of the Escherichia coli cell envelope that incorporate both membranes and various native membrane proteins. Our results predict that both the inner and outer membranes curve in a manner dependent on the size of the embedded proteins. The tightly cross-linked lipopolysaccharide molecules (LPS) of the outer membrane cause a strong coupling between the movement of proteins and lipids. While the flow of phospholipids is more random, their diffusion is nevertheless influenced by nearby proteins. Our results reveal protein-induced lipid sorting, whereby cardiolipin is significantly enriched within the vicinity of the water channel AqpZ and the multidrug efflux pump AcrBZ. In summary, our results provide unprecedented details of the intricate relationship between both membranes of E. coli and the proteins embedded within them.

The role of the peptides at the origin of life

The peptides in biosystems are polymers of L-amino acids, but they racemize slowly by an active isomerization kinetics. The chemical reactions in biosystems are, however, reversible and here we show by a thermodynamics analysis and by comprehensive Molecular Dynamics simulations of models of peptides, that the isomerization kinetics racemizes the peptides at high water activity, in agreement with experimental observations of aging of peptides, but enhances homochirality at a smaller water activity. The main conclusion of the simulations is that it is only possible to obtain and maintain homochirality in the presence of a hydrophobic compact core in a peptide of hundreds of chiral units and at a low water activity, and thus the establishment of homochirality at the origin of life and aging of proteins in biosystems might be strongly connected.

Distribution and Dynamic Properties of Xenon Dissolved in the Ionic Smectic Phase of [C16mim][NO3]: MD Simulation and Theoretical Model.

We have investigated the structural and dynamic properties of Xe dissolved in the ionic liquid crystal (ILC) phase of 1-hexadecyl-3-methylimidazolium nitrate using classical molecular dynamics (MD) simulations. Xe is found to be preferentially dissolved within the hydrophobic environment of the alkyl chains rather than in the ionic layers of the smectic phase. The structural parameters and the estimated local diffusion coefficients concerning the short-time motion of Xe are used to parametrize a theoretical model based on the Smoluchowski equation for the macroscopic dynamics across the smectic layers, a feature which cannot be directly obtained from the relatively short MD simulations. This protocol represents an efficient combination of computational and theoretical tools to obtain information on slow processes concerning the permeability and diffusivity of the xenon in smectic ILCs.

Analysis of the solution structure of Thermosynechococcus elongatus photosystem I in n-dodecyl-β-d-maltoside using small-angle neutron scattering and molecular dynamics simulation

Small-angle neutron scattering (SANS) and molecular dynamics (MD) simulation were used to investigate the structure of trimeric photosystem I (PSI) from Thermosynechococcus elongatus (T. elongatus) stabilized in n-dodecyl-β-d-maltoside (DDM) detergent solution. Scattering curves of detergent and protein–detergent complexes were measured at 18% D2O, the contrast match point for the detergent, and 100% D2O, allowing observation of the structures of protein/detergent complexes. It was determined that the maximum dimension of the PSI–DDM complex was consistent with the presence of a monolayer belt of detergent around the periphery of PSI. A dummy-atom reconstruction of the shape of the complex from the SANS data indicates that the detergent envelope has an irregular shape around the hydrophobic periphery of the PSI trimer rather than a uniform, toroidal belt around the complex. A 50ns MD simulation model (a DDM ring surrounding the PSI complex with extra interstitial DDM) of the PSI–DDM complex was developed for comparison with the SANS data. The results suggest that DDM undergoes additional structuring around the membrane-spanning surface of the complex instead of a simple, relatively uniform belt, as is generally assumed for studies that use detergents to solubilize membrane proteins.

An insight into the role of the grain boundary in plastic deformation by means of a bicrystalline pillar compression test and atomistic simulation

A combination of experimental and molecular dynamics (MD) simulations is used to investigate the interaction of dislocations with a selected grain boundary (GB) in bicrystalline pillars (BCPs) with component crystals oriented for single slip and multiple slip. As a reference, single-crystalline pillars with the same orientations are also tested and compared with the BCPs. Orientations identical to the experiments are used to generate models in MD simulations. Further, electron backscatter diffraction (EBSD) measurements on the cross-section of the pillars are performed to investigate the crystal lattice rotation in correlation with the excess dislocation density. A clear change in mechanical behavior of the BCP was observed when the size of the component crystals reduced below 1μm. The EBSD analyses of these small BCPs showed an increase in the misorientation in the vicinity of the GB. MD simulation provided atomistic insights into the dislocation nucleation process and the BCPs’ interaction with the GB. On the basis of these observations, it is concluded that in BCPs smaller than 1μm the dislocation–GB interaction plays a more crucial role than the dislocation–dislocation interaction.

The development of a surface defect machining method for hard turning processes

Hard turning (HT) is a material removal process employing a combination of a single point cutting tool and high speeds to machine hard ferrous alloys which exhibit hardness values over 45 HRC. In this paper, a surface defect machining (SDM) method for HT is proposed which harnesses the combined advantages of porosity machining and pulsed laser pre-treatment processing. From previous experimental work, this was shown to provide better controllability of the process and improved quality of the machined surface. While the experiments showed promising results, a comprehensive understanding of this new technique could only be achieved through a rigorous, in depth theoretical analysis. Therefore, an assessment of the SDM technique was carried out using both finite element method (FEM) and molecular dynamics (MD) simulations.FEM modelling was used to compare the conventional HT of AISI 4340 steel (52 HRC) using an Al2O3 insert with the proposed SDM method. The simulations showed very good agreement with the previously published experimental results. Compared to conventional HT, SDM provided favourable machining outcomes, such as reduced shear plane angle, reduced average cutting forces, improved surface roughness, lower residual stresses on the machined surface, reduced tool–chip interface contact length and increased chip flow velocity. Furthermore, a scientific explanation of the improved surface finish was revealed using a state-of-the-art MD simulation model which suggested that during SDM, a combination of both the cutting action and rough polishing action help improve the machined surface finish.

Volatile General Anesthetic Interactions with a Bacterial Sodium Channel

General anesthesia results from complex interactions involving ion channels in the brain. Voltage-gated ion channels are modulated by halogenated inhaled general anesthetics, however the drug-channel interactions are generally believed to be non-specific making it difficult to investigate the molecular mechanisms of anesthetic action. We find, however, that the bacterial sodium channel NaChBac exhibits differential regulation by different general anesthetics, suggesting that there may be specific interactions. Molecular dynamics (MD) simulations have identified several possible binding sites for isoflurane in the NaChBac channel structure. Here, we have characterized the affinity, occupancy and hydrogen bonding for these sites and identified key interactions. In addition, experimental evidence suggests that both isoflurane and sevoflurane have dual actions on NaChBac, possibly involving action at two different sites. Consistent with pore block, sevoflurane accelerates the decay of the current (20% faster at 0.4 mM sevoflurane) but, at the same time, increases the peak current (10% increase with 0.4 mM sevoflurane), which argues against the blocking mechanism. We hypothesize that an additional mechanism involving a distinct site is necessary to explain the latter effect. We are currently employing MD simulation and structural modeling combined with mutagenesis and electrophysiology to test this two-site hypothesis and investigate the molecular mechanisms of these opposing effects. Supported by NINDS F31 NS077689 (AFB) and NIGMS P01 GM0558 (MLK).

Molecular dynamics calculation of thermodynamic properties of iron solidification

The aim of this study is to identify the best available inter-atomic potentials for molecular dynamics (MD) calculation of solidification of iron and then to use the best potential to calculate thermodynamic properties such as equilibrium melting temperature, enthalpy, heat capacity and solid-liquid interfacial free energy. Our study reveals that embedded atom method (EAM) potential developed by Ackland et al. [2004 J. Phys.: Condens Matter. 16 S2629] appears to be the most accurate model for MD simulation of iron solidification. Simulations with the above EAM model predict the equilibrium melting temperature of iron is 1790K, the solid-liquid interfacial energy 214 mJ/m2. The difference with the experimental data is 1.2%, and 4.9% respectively.

Prediction of surface and adhesion energies of nanoimprint lithography materials and anti-sticking layers by molecular dynamics simulation

Molecular dynamics (MD) simulations are performed to calculate the surface and adhesion energies of nanoimprint lithography materials. The proposed simulation models include an amorphous SiO2, an amorphous poly(methylmethacrylate) film and self-assembled monolayers as anti-sticking layers. For the calculation of the surface and adhesion energies, a noble MD method is suggested to take into account the temperature effect, calculating the potential energy difference between the contacting and separate surfaces. The results of simulations are compared with the results of experiments obtained from liquid contact angle measurements and previous references. The relative error between simulations and experiments is about 10% for poly(methylmethacrylate) and self-assembled monolayers, and about 20% for amorphous SiO2, respectively. It is concluded that the suggested MD simulation model has given a satisfactory prediction of surface and adhesion energies and could provide more accurate results with the help of improved force fields.

Comparison between self‐guided Langevin dynamics and molecular dynamics simulations for structure refinement of protein loop conformations

This article presents a comparative analysis of two replica-exchange simulation methods for the structure refinement of protein loop conformations, starting from low-resolution predictions. The methods are self-guided Langevin dynamics (SGLD) and molecular dynamics (MD) with a Nosé-Hoover thermostat. We investigated a small dataset of 8- and 12-residue loops, with the shorter loops placed initially from a coarse-grained lattice model and the longer loops from an enumeration assembly method (the Loopy program). The CHARMM22 + CMAP force field with a generalized Born implicit solvent model (molecular-surface parameterized GBSW2) was used to explore conformational space. We also assessed two empirical scoring methods to detect nativelike conformations from decoys: the all-atom distance-scaled ideal-gas reference state (DFIRE-AA) statistical potential and the Rosetta energy function. Among the eight-residue loop targets, SGLD out performed MD in all cases, with a median of 0.48 Å reduction in global root-mean-square deviation (RMSD) of the loop backbone coordinates from the native structure. Among the more challenging 12-residue loop targets, SGLD improved the prediction accuracy over MD by a median of 1.31 Å, representing a substantial improvement. The overall median RMSD for SGLD simulations of 12-residue loops was 0.91 Å, yielding refinement of a median 2.70 Å from initial loop placement. Results from DFIRE-AA and the Rosetta model applied to rescoring conformations failed to improve the overall detection calculated from the CHARMM force field. We illustrate the advantage of SGLD over the MD simulation model by presenting potential-energy landscapes for several loop predictions. Our results demonstrate that SGLD significantly outperforms traditional MD in the generation and populating of nativelike loop conformations and that the CHARMM force field performs comparably to other empirical force fields in identifying these conformations from the resulting ensembles.

QM/MM studies of structural and energetic properties of the far-red fluorescent protein HcRed

The far-red fluorescent protein HcRed was investigated using molecular dynamics (MD) and combined quantum mechanics/molecular mechanics (QM/MM) calculations. Three models of HcRed (anionic chromophore) were considered, differing in the protonation states of nearby Glu residues (A: Glu214 and Glu146 both protonated; B: Glu214 protonated and Glu146 deprotonated; C: Glu214 and Glu146 both deprotonated). SCC-DFTB/MM MD simulations of model B yield good agreement with the available crystallographic data at ambient pH. Bond lengths in the QM region are well reproduced, with a root mean square (rms) deviation between experimental and average MD data of 0.079 A; the chromophore is almost co-planar, which is consistent with experimental observation; and the five hydrogen bonds involving the chromophore are conserved. QM/MM geometry optimizations were performed on representative snapshot structures from the MD simulations for each model. They confirm the structural features observed in the MD simulations. According to the DFT(B3LYP)/MM results, the cis-conformation of the chromophore is more stable than the trans-form by 9.1-12.9 kcal mol(-1) in model B, and by 12.4-19.9 kcal mol(-1) in model C, consistent with the experimental preference for the cis-isomer. However, in model A when both Glu214 and Glu146 are protonated, the stability is inverted with the trans-form being favored. The different protonation states of the titratable active-site residues Glu214 and Glu146 thus critically influence the manner in which the relative stability and degree of planarity of the cis- and trans-conformers vary with pH. Coupled with the known correlation of chromophore conformation with fluorescence efficiency, this work provides a detailed structural basis for the observed phenomenon that red fluorescent proteins such as HcRed, mKate and Rtms5 show bright fluorescence at high pH.