Detailed Molecular Dynamics Simulations Research Articles

Quantitative Prediction of the Structure and Viscosity of Aqueous Micellar Solutions of Ionic Surfactants: A Combined Approach Based on Coarse-Grained MARTINI Simulations Followed by Reverse-Mapped All-Atom Molecular Dynamics Simulations.

We address the problem of the quantitative prediction of micelle formation in dilute aqueous solutions of ionic surfactants using sodium dodecyl sulfate (SDS) as a model system through a computational approach that involves three steps: (a) execution of coarse-grained simulations based on the MARTINI force field (with slightly modified parameters to afford the formation of large micelles); (b) reverse mapping of the final self-assembled coarse-grained configuration into an all-atom configuration; and (c) final relaxation of this all-atom configuration through short-time (on the order of a few tens of nanoseconds), detailed isothermal-isobaric molecular dynamics simulations using the CHARMM36 force field. For a given concentration of the solution in SDS molecules, the modified MARTINI-based coarse-grained simulations lead to the formation of large micelles characterized by mean aggregation numbers above the experimentally observed ones. However, by reintroducing the detailed chemical structure through a strategy that solves a well-defined geometric problem and re-equilibrating, these large micellar aggregates quickly dissolve to smaller ones and equilibrate to sizes that perfectly match the average micelle size measured experimentally at the given surfactant concentration. From the all-atom molecular dynamics simulations, we also deduce the surfactant diffusivity DSDS and the zero-shear rate viscosity, η0, of the solution, which are observed to compare very favorably with the few experimental values that we were able to find in the literature.

Simulations of Active Transport Across the Blood-Brain Barrier

The blood-brain barrier (BBB) is responsible for maintaining homeostasis of the brain by regulating the chemical environment, immune cell transport, and the entry of toxins and pathogens, and misregulation of the BBB has been shown to be implicated in numerous CNS disorders. One of the challenges in studying the BBB include the bioavailability of therapies, as well as rising multidrug resistance of pathogens. A major contributor to drug resistance and lacking bioavailability of therapies is the over-expression of the broad-specificity P-glycoprotein (P-gp) efflux pump in the endothelial cells of the BBB. However, despite the role of P-gp in affecting the bioavailability, pharmacokinetics and efficacy of therapeutic drugs, the mechanism of the efflux of substrates via P-gp, as well as the inhibition of P-gp activity, are not well understood. To address the mechanisms of P-gp-mediated substrate efflux and P-gp inhibition, we performed multimicrosecond unbiased atomic detail molecular dynamics (MD) simulations of the P-glycoprotein from novel human cryo-EM models as well as X-ray crystal structures in the presence of substrates (doxorubicin, rhodamine-123) and an inhibitor (tariquidar). We compare the differential transport gradient of P-gp substrates and inhibitors between the inward-facing (IF) and outward-facing (OF) conformations of P-gp to propose a model of P-gp turnover. We compare this model of active transport to our model of passive transport across the BBB.

Epidermal Growth Factor Receptor Kinase Exon 19 Deletion Mutations Display Variability in Activation and Drug Responsiveness

Activating mutations in epidermal growth factor receptor (EGFR) kinase contribute to non-small cell lung carcinoma (NSCLC) in 10-35% of cases. Greater than 90% of these cases are due to an in-frame deletion within exon 19 (Ex19Del) or a leucine-to-arginine missense mutation on the activation loop (L858R). Recently, we demonstrated that a newly-identified resistance mutation, G724S, develops in Ex19Del but not L858R. Moreover, we found that specific variants of Ex19Del were more likely to develop G724S than others. Here, we use detailed molecular dynamics simulations to identify previously unidentified functional differences between EGFR Ex19Del variants. Our results have important implications for the management of patients with EGFR-mediated disease.

Integration of Atomistic Simulation with Experiment Using Time−Temperature Superposition for a Cross‐Linked Epoxy Network

AbstractFor glass‐forming polymers, direct quantitative comparison of atomistically detailed molecular dynamics simulations with thermomechanical experiments is hindered by the vast mismatch between the accessible timescales. Recently, the authors demonstrated the successful application of the time–temperature superposition (TTS) principle to perform such a comparison for the volumetric properties of an epoxy network. Here, the local translational dynamics of the same network is computationally followed‐up and studied. The mean squared displacement (MSD) and time‐scaling exponent trends of select atoms of the network are calculated over a temperature range that spans the glass transition. Using TTS, both trends collapse onto master curves that relate the reduced MSD and time‐scaling exponent to the reduced time at a reference temperature. Because the reduced time of these computational master curves extends to 109 s, they can be directly compared with experimental creep compliance for the same material from the literature. A quantitative comparison of the three master curves is performed to provide an integrated view that relates atomic‐level dynamics with macroscopic thermomechanics. The time‐shift factors needed for TTS in simulation show excellent agreement with experiment in the literature, further establishing the veracity of the approach.

Mechanical properties of hydrogenated amorphous silicon (a-Si:H) particles

A nanoindenter was used to compress individual particles of hydrogenated amorphous silicon (a-Si:H) ranging in diameter from 290 nm to 780 nm. The colloidal synthesis used to produce the particles enables the hydrogen content to be manipulated over a wide range, from about 5 at. % to 50 at. %, making these a-Si:H particles promising for applications in lithium ion batteries, hydrogen storage, and optical metamaterials. Force-displacement curves generated using a tungsten probe flattened with focused ion beam exhibited elastic and then plastic deformations, followed by fracture and crushing of the particles. For particles with 5% and 50% H, Young's moduli, yield strengths, and compressive strengths were 73.5(±19.5) GPa, 5.8 GPa, and 3.2(±0.1)–9.3(±0.6) GPa and 31.2(±9.0) GPa, 2.5 GPa, and 1.8 (±0.3)–5.3(±0.8) GPa, respectively. Particles with more hydrogen were significantly more compliant and weaker. This is consistent with atomistically detailed molecular dynamics simulations, which revealed compression forms of an interphase of H atom clusters that weakens the material.

Comparing hydrothermal sintering and cold sintering process: Mechanisms, microstructure, kinetics and chemistry

This study reports the sintering of zinc oxide (ZnO) through the comparison between the hydrothermal sintering (HS) and the cold sintering process (CSP) operating in closed and open conditions, respectively. Sintering was performed at 155 ± 5 °C applying a pressure of 320 MPa, and during different holding times (0 min, 20 min, 40 min and 80 min). Whatever the low sintering process used, ceramics characteristics are almost similar in terms of relative densities and ZnO structure. However, several differences such as the nature of stabilized phases, grain sizes and quantities of residual molecules in the densified pellets, were characterized and explained. The formation of zinc acetate “bridges” was observed ex situ in hydrothermally sintered samples. A detailed ReaxFF molecular dynamics simulation was performed to help understand the formation mechanisms of zinc acetate “bridges” and compare the chemical activities between HS and CSP.

Anomalous viscoelastic response of water-dimethyl sulfoxide solution and a molecular explanation of non-monotonic composition dependence of viscosity.

Amphiphilic molecules such as dimethyl sulfoxide (DMSO) and its aqueous binary mixtures exhibit pronounced nonideality in composition dependence of several static and dynamic properties. We carry out detailed molecular dynamics simulations to calculate various properties including viscosity of the mixture and combine the results with a mode coupling theory analysis to show that this nonideality can be attributed to local structures that are stable on a short time scale but transient on a long time scale to maintain the large scale homogeneity of the solution. Although the existence of such quasistable structures has been deciphered from spectroscopy, a detailed characterization does not exist. We calculate stress-stress autocorrelation functions (SACFs) of water-DMSO binary mixtures. We employ two different models of water, SPC/E and TIP4P/2005, to check the consistency of our results. Viscosity shows a pronounced nonmonotonic composition dependence. The calculated values are in good agreement with the experimental results. Fourier transform of SACF provides frequency-dependent viscosity. The frequency-dependent viscosity (that is, viscoelasticity) is also found to be strongly dependent on composition. Viscoelasticity exhibits sharp peaks due to intramolecular vibrational modes of DMSO, which are also seen in the density of states. We evaluate the wavenumber dependent dynamic structure factor and wavenumber dependent relaxation time. The latter also exhibits a sharp nonmonotonic composition dependence. The calculated dynamic structure factor is used in mode coupling theory expression of viscosity to obtain a semiquantitative understanding of anomalous composition dependence of viscosity. Both the self-diffusion coefficients and rotational correlation times of water and DMSO molecules exhibit nonmonotonic composition dependence.

Coarse-graining molecular dynamics: stochastic models with non-Gaussian force distributions

Incorporating atomistic and molecular information into models of cellular behaviour is challenging because of a vast separation of spatial and temporal scales between processes happening at the atomic and cellular levels. Multiscale or multi-resolution methodologies address this difficulty by using molecular dynamics (MD) and coarse-grained models in different parts of the cell. Their applicability depends on the accuracy and properties of the coarse-grained model which approximates the detailed MD description. A family of stochastic coarse-grained (SCG) models, written as relatively low-dimensional systems of nonlinear stochastic differential equations, is presented. The nonlinear SCG model incorporates the non-Gaussian force distribution which is observed in MD simulations and which cannot be described by linear models. It is shown that the nonlinearities can be chosen in such a way that they do not complicate parametrization of the SCG description by detailed MD simulations. The solution of the SCG model is found in terms of gamma functions.

Molecular Dynamics Simulation Study of Adsorption of Bioinspired Oligomers on Alumina Surfaces.

The adsorption of small oligomers on a model metal oxide surface was studied with atomistically detailed molecular dynamics simulations. The oligomers consisted of two different repeat units: a maleimide, which contains a catechol functional group as in the dopamine residue found in marine adhesive proteins, and a methyl acrylate. A hydroxylated alumina surface was used as the model metal oxide surface. Adsorption interactions were investigated in aqueous as well as anhydrous conditions. In anhydrous conditions, the model oligomers displayed strong adsorption interactions with the surface. However, in aqueous conditions, the adsorption interactions were significantly weakened because of the competition with the water molecules for adsorption sites near the surface. Catechol functional groups in the model oligomers were found to play an important role in adsorption interactions with the alumina surface via hydrogen bonds. However, diverse adsorption properties were observed depending on compositions and sequences of two different repeat units and self-aggregations, indicating that the hydrogen bonding capability of catechol groups is not the sole factor determining adsorption properties.

High Polymer Mass Densities at the Mouths of Carbon Nanotubes (CNTs) Control the Diffusion of Small Molecules through CNT-Based Polymer Nanocomposite Membranes.

Detailed molecular dynamics (MD) simulations of model single-walled carbon nanotube (CNT) membranes based on atactic poly(methyl methacrylate) (aPMMA) indicate that PMMA chains significantly penetrate nanotubes through their faces. They predict very high-density values of the polymer in the interfacial area around the CNT mouths that can exceed by 50% the density of the bulk polymer at the same thermodynamic conditions. This dramatically decreases the diffusivity of relatively small penetrants (in our study, water molecules) in the nanocomposite membrane, because of the exceedingly long times needed by these small molecules to diffuse through such a dense interfacial layer before accessing the interior of the nanotubes where they can travel really fast. According to our simulations, the escape time of a confined water molecule from the blocked mouths of a CNT can exceed by several orders of magnitude the time needed by the same molecule to move through the CNT pore. Our work indicates the importance of completely avoiding (or at least minimizing) penetration of polymer chains into the CNT pores through the mouths of the tubes in enabling the efficient transport of small- to moderate-size molecules in model CNT-based polymer membranes, since this provides the highest resistance to their mobility through the membrane.

Electrification in granular gases leads to constrained fractal growth

The empirical observation of aggregation of dielectric particles under the influence of electrostatic forces lies at the origin of the theory of electricity. The growth of clusters formed of small grains underpins a range of phenomena from the early stages of planetesimal formation to aerosols. However, the collective effects of Coulomb forces on the nonequilibrium dynamics and aggregation process in a granular gas – a model representative of the above physical processes – have so far evaded theoretical scrutiny. Here, we establish a hydrodynamic description of aggregating granular gases that exchange charges upon collisions and interact via the long-ranged Coulomb forces. We analytically derive the governing equations for the evolution of granular temperature, charge variance, and number density for homogeneous and quasi-monodisperse aggregation. We find that, once the aggregates are formed, the granular temperature of the cluster population, the charge variance of the cluster population and the number density of the cluster population evolve in such a way that their non-dimensional combination obeys a physical constraint of nearly constant dimensionless ratio of characteristic electrostatic to kinetic energy. This constraint on the collective evolution of charged clusters is confirmed both by our theory and our detailed molecular dynamics simulations. The inhomogeneous aggregation of monomers and clusters in their mutual electrostatic field proceeds in a fractal manner. Our theoretical framework is extendable to more precise charge exchange mechanisms, a current focus of extensive experimentation. Furthermore, it illustrates the collective role of long-ranged interactions in dissipative gases and can lead to novel designing principles in particulate systems.

Oxygen Dynamics in Transition Metal-Doped Bismuth Oxides

A detailed quasielastic neutron scattering (QENS) study provides direct insights into the mechanism of ionic conduction in the type II transition metal-doped bismuth oxides Bi22W5O48, Bi22Nb5O45.5, and Bi22W2.5Nb2.5O46.75. Quantitative analysis of the QENS broadening reveals an oscillating behavior similar to that observed recently for pure fluorite-type δ-Bi2O3, which can be adequately modeled by a coherent adaption of the Chudley-Elliott jump diffusion model. In conjunction with detailed ab initio molecular dynamics simulations, this shows that oxygen diffuses through these compounds almost exclusively within fluorite-type regions via an isotropic, liquid-like mechanism. The average oxygen jump length is slightly shorter than half the length of the fluorite-type subcell; this is attributed to the flexible coordination environments around Bi, in contrast to the more regular coordination environments around the transition-metal dopants, which localize vacancies and prevent the remaining oxygen atoms from contributing to the overall oxygen diffusivity.

Structure-property relations characterizing the devitrification of Ni-Zr glassy alloy thin films

The investigation of devitrification in thermally annealed nanodimensional glassy alloy thin films provides a comprehensive understanding of their thermal stability, which can be used to explore potential applications. The amorphous to crystalline polymorphous transformation of cosputtered Ni-Zr alloy (Ni78Zr22 at. %) films, with a thickness lower than the reported critical limit of devitrification, was studied through detailed structural characterization and molecular dynamics (MD) simulations. Devitrification to a nanocrystalline state (Ni7Zr2 structure) was observed at 800 °C, with an increase in density (∼3.6%) much higher than that achieved in bulk alloys. Variation in the magnetic property of the films and the overall physical structure including morphology and composition were examined before and after annealing. MD simulations were employed to effectively elucidate not only the high densification but also the increased magnetic moment after annealing, which was correlated with the simulated change in the coordination number around Ni atoms. The structural relaxation process accompanying devitrification was described as a disorder-to-order transformation while highlighting the crucial role played by chemical short range order prevalent in glassy materials.

Energy landscape of the domain movement in Staphylococcus aureus UDP-N-acetylglucosamine 2-epimerase

Staphylococcus aureus is an important cause of resistant healthcare-associated infections. It has been shown that the wall teichoic acid (WTA) may be an important drug target acting on antibiotic-resistant cells. The UDP-N-acetylglucosamine 2-epimerase, MnaA, is one of the first enzymes on the pathway for the biosynthesis of the WTA. Here, detailed molecular dynamics simulations of S. aureus MnaA were used to characterize the conformational changes that occur in the presence of UDP and UDP-GlcNac and also the energetic landscape associated with these changes. Using different simulation techniques, such as ABMD and GAMD, it was possible to assess the energetic profile for the protein with and without ligands in its active site. We found that there is a dynamic energy landscape that has its minimum changed by the presence of the ligands, with a closed structure of the enzyme being more frequently observed for the bound state while the unbound enzyme favors an opened conformation. Further structural analysis indicated that positively charged amino acids associated with UDP and UDP-GlcNac interactions play a major role in the enzyme opening movement. Finally, the energy landscape profiled in this work provides important conclusions for the design of inhibitor candidates targeting S. aureus MnaA.

An experimentally validated approach to calculate the blood-brain barrier permeability of small molecules

Drug development for the treatment of central nervous system (CNS) diseases is extremely challenging, in large part due to the difficulty in crossing the blood-brain barrier (BBB). Here we develop and experimentally validate a new in silico method to predict quantitatively the BBB permeability for small-molecule drugs. We show accurate prediction of solute permeabilities at physiological temperature using high-temperature unbiased atomic detail molecular dynamics simulations of spontaneous drug diffusion across BBB bilayers. These simulations provide atomic detail insights into the transport mechanisms, as well as converged kinetics and thermodynamics. The method is validated computationally against physiological temperature simulations for fast-diffusing compounds, as well as experimentally by direct determination of the compound permeabilities using a transwell assay as an in vitro BBB model. The overall agreement of the predicted values with both direct simulations at physiological temperatures and experimental data is excellent. This new tool has the potential to replace current semi-empirical in silico screening and in vitro permeability measurements in CNS drug discovery.

Simulation-Guided Rational de Novo Design of a Small Pore-Forming Antimicrobial Peptide.

In the age of failing small-molecule antibiotics, tapping the near-infinite structural and chemical repertoire of antimicrobial peptides (AMPs) offers one of the most promising routes toward developing next-generation antibacterial compounds. One of the key impediments en route is the lack of methodologies for systematic rational design and optimization of new AMPs. Here we present a new simulation-guided rational design approach and apply it to develop a potent new AMP. We show that unbiased atomic detail molecular dynamics (MD) simulations are able to predict structures formed by evolving peptide designs enabling structure-based rational fine-tuning of functional properties. Starting from a 14-residue poly leucine template we demonstrate the design of a minimalistic potent new AMP. Consisting of only four types of amino acids (LDKA), this peptide forms large pores in microbial membranes at very low peptide-to-lipid ratios (1:1000) and exhibits low micromolar activity against common Gram-positive and Gram-negative pathogenic bacteria. Remarkably, the four amino acids were sufficient to encode preferential poration of bacterial membranes with negligible damage to red blood cells at bactericidal concentrations. As the sequence is too short to span cellular membranes, pores are formed by stacking of channels in each bilayer leaflet.

A Molecular Dynamics Based Comparison of the Mechanical Properties of Three Polytypes of Cubic BC3

In this work molecular dynamics simulations are employed to compare the mechanical properties and hardness of three polytypes of cubic BC3. Firstly, two interatomic Tersoff potentials, with different parameterizations, were identified from the literature for the boron-carbon system. Based on cohesive energies and structural properties from existing ab-initio studies, the suitability of the two potentials for predicting the properties of BC3 was analyzed. Secondly, using the better interatomic potential, more detailed molecular dynamics simulations were conducted to estimate and compare the elastic, yield, post-yield behavior and hardness of the three polytypes. The elastic constants compare well with existing abinitio values and vary by at most by 15% amongst the three polytypes. Response to indentation showed considerable qualitative differences in yield and post-yield response. One of the polytypes showed lower yield strength and seemed more ductile than the other two. The hardness also showed a complex dependence on both the material and the indentation depths. A peculiar, indenter-size dependent pile-up behavior was also seen. Specifically, for lower radii, pile-up was seen on indentation. As the radius of the indenter was increased, pile-up was seen only on retracting the indenter. The higher volume occupied by the indentation-amorphized material was found to be the reason for pile-up on retracting the indenter.

Early Translocation of Anthrax Lethal Factor: Kinetics from Molecular Dynamics Simulations and Milestoning Theory

We report atomically detailed simulations of the early translocation events of the lethal factor (LF) through the anthrax channel. Anthrax is a serious infectious disease caused by the bacterium known as Bacillus anthracis. The anthrax toxin consists of three proteins: protective antigen (PA), LF and edema factor (EF). PA is cleaved by a furin-related protease to generate PA63. PA63 then oligomerizes and forms a prepore complex that competitively binds LF or EF. The complex is then endocytosed and a PA channel is formed under the acidic condition in the endosome. The PA channel translocates LF and EF into cytosol, resulting in the death of the cell. The overall delivery of LF from endosome to cytosol can be divided into two major steps: pore formation, and translocation. Many experiments were conducted to differentiate between factors that influence the delivery of LF. However, an atomically detailed understanding of the function of the LF translocation machinery is missing. Here we focus on the first steps of the translocation step. We describe atomically detailed molecular dynamics simulations of the translocation of the LF N-terminal segment (LFN) through the wild type and mutated PA channels. The kinetics and thermodynamic properties of the early events of the translocation process are computed within the Milestoning theory. We illustrate that the initial event is strongly influenced by the protonation states of the permeating LFN. At the limit of maximum protonation, the free energy profile of the LFN translocation suggests that the system operates like a ratchet. Several mutants of the channel illustrate that long-range electrostatic interactions provide the dominant driving force for the translocation, while mutants with variable sizes cause smaller effects on translocation. Our simulation results agree qualitatively with published experimental results.

Self-assembly and structural manipulation of diblock-copolymer grafted nanoparticles in a homopolymer matrix

Detailed coarse-grained molecular dynamics simulations are performed to investigate the structural and mechanical properties of nanoparticles (NPs) grafted with an amphiphilic AB diblock copolymer, with the A-block being compatible with NPs and the B-block being miscible with a homopolymer matrix. We systematically investigate the effects of the grafting density (Ng), the component ratio (α) and the flexibility of the grafted diblock copolymer on the structural and mechanical properties of polymer nanocomposites (PNCs). Interestingly, we observe that the grafted NPs can form a core-shell like structure attributed to the adsorption of the A-blocks onto the NPs, validated by the radial distribution function of the A and B blocks away from the surface of the NPs. The integrity of the core-shell structure is influenced by the grafting density and the component ratio of the grafted chains. The core-shell structure of the NPs becomes more perfect with greater Ng. The morphology of the NPs is shifted from a network structure to an isolated or well dispersed state upon increasing the grafting density. Meanwhile, we analyze the evolution of the morphology of the NPs during the uniaxial tensile process by calculating the number of neighboring NPs as a function of strain, thus finding that the NP network is broken-up at low grafting density, while only a little change is observed at high grafting density. Upon increasing the component ratio of the B-block to the A-block, the dispersion of the NPs becomes better, characterized by the radial distribution function of NPs-NPs, NPs-A-blocks, NPs-B-blocks, NPs-matrix, the number of neighboring NPs and the snapshots. Lastly, by changing the B-block from being flexible to stiff, the core-shell structure of the NPs disappears after the formation of a typical capsule morphology. This capsule-ordered structure becomes more prominent with the increase in Ng. Remarkably, compared to the effect of the core-shell morphology on the mechanical properties, the capsule morphology reinforces the mechanical properties more obviously. In general, this simulation work provides a deep insight into the structural and mechanical properties of NPs grafted with diblock copolymer chains, in the hope of providing some guidance on the design and preparation of high-performance PNCs.

Ionic conductivity in aqueous electrolyte solutions: Insights from computer simulations

There exist a large amount of data on conductivity of various ions in aqueous and non-aqueous solvents as a function of ionic radius, pressure, temperature, ionic concentration, etc. Because of its importance in chemistry, biology, electrochemistry and a number of other areas, a consistent picture of how the various factors influence the conductivity is essential. We present detailed molecular dynamics simulations of ions in water in order to understand the influence of three factors: (i) ionic radius (ii) temperature and (iii) pressure. We propose an alternative explanation for the variation of ionic conductivity as a function of ionic radius for ions in water. The explanation is based on the Levitation Effect which arises from mutual cancellation of forces on the diffusant or ions when the ions are of the same radius as the bottleneck present in the solvent. This theoretical framework not only accounts for the variation of conductivity with ionic radius but also its variation with pressure. Experimental data on variation of ionic conductivity shows contrasting dependence on pressure for ions of different radius. We show that the proposed theoretical framework also accounts for the variation of ionic conductivity as a function of pressure for ions of different radius. Thus, we have been able to propose a theoretical framework which unifies our understanding of three different factors, namely, ionic radius, temperature and pressure.