Computing aspects of molecular dynamics simulation

Ni sintering in the Ni/YSZ porous anode of a solid oxide fuel cell changes the porous structure, leading to degradation. Preventing sintering and degradation during operation is a great challenge. Usually, a sintering molecular dynamics (MD) simulation model consisting of two particles on a substrate is used; however, the model cannot reflect the porous structure effect on sintering. In our previous study, a multi-nanoparticle sintering modeling method with tens of thousands of atoms revealed the effect of the particle framework and porosity on sintering. However, the method cannot reveal the effect of the particle size on sintering and the effect of sintering on the change in the porous structure. In the present study, we report a strategy to reveal them in the porous structure by using our multi-nanoparticle modeling method and a parallel large-scale multimillion-atom MD simulator. We used this method to investigate the effect of YSZ particle size and tortuosity on sintering and degradation in the Ni/YSZ anodes. Our parallel large-scale MD simulation showed that the sintering degree decreased as the YSZ particle size decreased. The gas fuel diffusion path, which reflects the overpotential, was blocked by pore coalescence during sintering. The degradation of gas diffusion performance increased as the YSZ particle size increased. Furthermore, the gas diffusion performance was quantified by a tortuosity parameter and an optimal YSZ particle size, which is equal to that of Ni, was found for good diffusion after sintering. These findings cannot be obtained by previous MD sintering studies with tens of thousands of atoms. The present parallel large-scale multimillion-atom MD simulation makes it possible to clarify the effects of the particle size and tortuosity on sintering and degradation.

Calcium-dependent lectin I from Pseudomonas aeruginosa (PA-IL) binds specifically to oligosaccharides presenting an alpha-galactose residue at their nonreducing end, such as the disaccharides alphaGal1-2betaGalOMe, alphaGal1-3betaGalOMe, and alphaGal1-4betaGalOMe. This provides a unique model for studying the effect of the glycosidic linkage of the ligands on structure and thermodynamics of the complexes by means of experimental and theoretical tools. The structural features of PA-IL in complex with the three disaccharides were established by docking and molecular dynamics simulations and compared with those observed in available crystal structures, including PA-IL.alphaGal1-2betaGalOMe complex, which was solved at 2.4 A resolution and reported herein. The role of a structural bridge water molecule in the binding site of PA-IL was also elucidated through molecular dynamics simulations and free energy calculations. This water molecule establishes three very stable hydrogen bonds with O6 of nonreducing galactose, oxygen from Pro-51 main chain, and nitrogen from Gln-53 main chain of the lectin binding site. Binding free energies for PA-IL in complex with the three disaccharides were investigated, and the results were compared with the experimental data determined by titration microcalorimetry. When the bridge water molecule was included in the free energy calculations, the simulations predicted the correct binding affinity trends with the 1-2-linked disaccharide presenting three times stronger affinity ligand than the other two. These results highlight the role of the water molecule in the binding site of PA-IL and indicate that it should be taken into account when designing glycoderivatives active against P. aeruginosa adhesion.

Praziquantel (PZQ) is one of the most widespread anthelmintic drugs. However, the frequent insufficient application of PZQ after oral administration is associated with its low solubility, penetration rate, and bioavailability. In the present study, the permeation of PZQ through a 1,2-dioleoyl- sn-glycero-3-phosphocholine (DOPC) membrane was investigated to probe glycyrrhizin-assisted transport. Glycyrrhizin (or glycyrrhizic acid, GA), a natural saponin, shows the ability to enhance the therapeutic activity of various drugs when it is used as a drug delivery system. However, the molecular mechanism of this effect is still under debate. In the present study, the transport rate was measured experimentally by a parallel artificial membrane permeation assay (PAMPA) and molecular dynamics (MD) simulation with DOPC lipid bilayers. The formation of the noncovalent supramolecular complex of PZQ with disodium salt of GA (Na2GA) in an aqueous solution was proved by the NMR relaxation technique. PAMPA experiments show a strong increase in the amount of the penetrating praziquantel molecules in comparison with a saturated aqueous solution of pure drug used as a control. MD simulation of PZQ penetration through the bilayer demonstrates an increase in permeability into the membrane in the presence of a glycyrrhizin molecule. A decrease in the free energy barrier in the middle of the lipid bilayer was obtained, associated with the hydrogen bond between PZQ and GA. Also, GA reduces the local bilayer surface resistance to penetration of PZQ by rearranging the surface lipid headgroups. This study clarifies the mechanism of increasing the drug's bioavailability in the presence of glycyrrhizin.

The term molecular mechanics (MM) refers to the use of simple potential-energy functions (e.g., harmonic oscillator or Coulombic potentials) to model molecular systems. Molecular mechanics approaches are widely applied in molecular structure refinement, molecular dynamics (MD) simulations, Monte Carlo (MC) simulations, and ligand-docking simulations. Typically, molecular mechanics models consist of spherical atoms connected by springs which represent bonds. Internal forces experienced in the model structure are described using simple mathematical functions. For example, Hooke’s law is commonly used to describe bonded interactions, and the nonbonded atoms might be treated as inelastic hard spheres or may interact according to a Lennard-Jones potential. Using these simple models, a molecular dynamics simulation numerically solves Newton’s equations of motion, thus allowing structural fluctuations to be observed with respect to time. Dynamic simulation methods are widely used to obtain information on the time evolution of conformations of proteins and other biological macromolecules1–4 and also kinetic and thermodynamic information. Simulations can provide fine detail concerning the motions of individual particles as a function of time. They can be utilized to quantify the properties of a system at a precision and on a time scale that is otherwise inaccessible, and simulation is, therefore, a valuable tool in extending our understanding of model systems. Theoretical consideration of a system additionally allows one to investigate the specific contributions to a property through “computational alchemy”,5 that is, modifying the simulation in a way that is nonphysical but nonetheless allows a model’s characteristics to be probed. One particular example is the artificial conversion of the energy function from that representing one system to that of another during a simulation. This is an important technique in free-energy calculations.6 Thus, molecular dynamics simulations, along with a range of complementary computational approaches, have become valuable tools for investigating the basis of protein structure and function. This review offers an outline of the origin of molecular dynamics simulation for protein systems and how it has developed into a robust and trusted tool. This review then covers more recent advances in theory and an illustrative selection of practical studies in which it played a central role. The range of studies in which MD has played a considerable or pivotal role is immense, and this review cannot do justice to them; MD simulations of biomedical importance were recently reviewed.4 Particular emphasis will be placed on the study of dynamic aspects of protein recognition, an area where molecular dynamics has scope to provide broad and far-ranging insights. This review concludes with a brief discussion of the future potential offered to advancement of the biological and biochemical sciences and the remaining issues that must be overcome to allow the full extent of this potential to be realized. 1.1. Historical Background MD methods were originally conceived within the theoretical physics community during the 1950s. In 1957, Alder and Wainwright7 performed the earliest MD simulation using the so-called hard-sphere model, in which the atoms interacted only through perfect collisions. Rahman8 subsequently applied a smooth, continuous potential to mimic real atomic interactions. During the 1970s, as computers became more widespread, MD simulations were developed for more complex systems, culminating in 1976 with the first simulation of a protein9,10 using an empirical energy function constructed using physics-based first-principles assumptions. MD simulations are now widely and routinely applied and especially popular in the fields of materials science11,12 and biophysics. As will be discussed later in this review, a variety of experimental conditions may be simulated with modern theories and algorithms. The initial simulations only considered single molecules in vacuo. Over time, more realistic or at least biologically relevant simulations could be performed. This trend is continuing today. The initial protein MD simulation, of the small bovine pancreatic trypsin inhibitor (BPTI), covered only 9.2 ps of simulation time. Modern simulations routinely have so-called equilibration periods much longer than that, and production simulations of tens of nanoseconds are routine, with the first microsecond MD simulation being reported in 1998.13 In addition, the original BPTI simulation included only about 500 atoms rather than the 104-106 atoms that are common today. While much of this advancement results from an immense increase in availability of computing power, major theoretical and methodological developments also contribute significantly. The number of publications regarding MD theory and application of MD to biological systems is growing at an extraordinary pace. A single review cannot do justice to the recent applications of MD. Using data from ISI Web of Science, the authors estimate that during 2005 at least 800 articles will be published that discuss molecular dynamics and proteins. The historical counts are shown in Figure 1. Open in a separate window Figure 1 Articles matching ISI Web of Science query “TS=(protein) AND TS=(molecular dynamics)”.

Selectivity and transport in aquaporins from molecular simulation studies.

We have designed a time-space multiresolution approach for large-scale molecular-dynamics (MD) simulations involving long-range Coulomb forces and three-body interactions. This approach has been implemented on various parallel architectures including the 512-node Intel Touchstone Delta at Caltech and the 128-processor IBM SP1 at Argonne National Laboratory. Parallel MD simulations involving 1.12-million particles have been performed to investigate the pore interface growth and the roughness of fracture surfaces in porous silica. When the mass density is reduced to a critical value, pores grow catastrophically to cause fracture. The roughness exponent for internally fractured surfaces, {alpha} = 0.87 {+-} 0.02, supports experimental claims about the universality of {alpha}. A reliable interatomic potential has been developed for MD simulations Of Si{sub 3}N{sub 4}. The nature of phonon densities-of-states due to low-energy floppy modes in crystalline and glassy states has been investigated. Floppy modes appear continuously in the glass as the connectivity of the system is reduced. In the crystal, they appear suddenly at 30% volume expansion. The density-of-states due to floppy modes varies linearly with energy, and the specific heat is significantly enhanced by these modes. Thermal conductivities of ceramic materials are calculated with a nonequilibrium MD method and the Kubo-Greenwood formula using a parallel eigensolver and the parallel MD approach. The calculations for amorphous silica agree well with experiments over a very wide range of temperatures above the plateau region. Currently, we are investigating thermal transport mechanisms in technologically important materials - porous glasses, nanophase ceramics, and zeolites.

Research on novel co-crystals has long been a focal point in the field of high-energy material modification. In the present exploration, density functional theory (DFT) and molecular dynamics (MD) simulations were employed to investigate the properties of pentaerythritol tetranitrate (PETN)/3,4-dinitrofurazanofurazan (DNTF) mixtures across a molar fraction interval of 9:1 to 1:9. This study incorporated a comprehensive analysis of multiple key characteristics, encompassing the surface electrostatic potential of molecules, atomic interaction lines, binding energy values, trigger bond lengths, cohesive energy density, together with the mechanical behaviors of the designated assembly. Additionally, the detonation characteristics of pure PETN, pure DNTF, and the PETN/DNTF system were predicted using the EXPLO-5 software in conjunction with the nitrogen equivalent coefficient (NEC) method. The outcomes of the study uncovered significant divergences in the surface electrostatic potential of PETN versus DNTF molecules. These disparities indicate that intermolecular interactions across different molecular species are stronger than the interactions within homogeneous molecular groups, which in turn points to the viability of co-crystal synthesis between PETN and DNTF. A peak value of binding energy was ascertained at a molar ratio of 3:7, indicating the highest likelihood of co-crystal formation at this composition. The primary driving forces for co-crystallization were identified as electrostatic forces and van der Waals forces. The as-obtained co-crystal explosive demonstrated modest sensitivity and intermediate mechanical behavior. In a similar vein, the detonation behavior of the co-crystal at a molar ratio of 3:7 fell between that of pure PETN and pure DNTF, positioning it as a novel type of insensitive high-energy material. Materials Studio software was utilized to forecast the characteristics of PETN/DNTF co-crystals with varying molar ratios and crystal planes via molecular dynamics (MD) simulations. The MD simulations were performed with a time step of 1 femtosecond (fs) and a total simulation duration of 2ns (ns). An isothermal-isobaric (NPT) ensemble was employed for the 2ns MD simulations. The COMPASS force field was adopted, with the temperature set at 295 Kelvin (K). For the prediction of detonation characteristics, the EXPLO-5 software was combined with the nitrogen equivalent coefficient (NEC) method.

Introduction: Milk kefir, a fermenting milk made with kefir grains, has shown potential in promoting apoptosis, regulating the cell cycle, and reducing tumor growth in breast cancer cells. This study aimed to investigate the stability and potential of milk kefir metabolites as inhibitors of breast cancer growth by interacting with the estrogen receptor alpha (ER-α), a key protein involved in breast cancer cell proliferation. We used computational methods, specifically molecular docking simulations with AutoDock and molecular dynamics (MD) simulations with Gromacs, to analyze how these metabolites bind to ER-α. Methods: A combination of molecular docking and MD simulations was used to explore how metabolites derived from milk kefir interact with ER-α, a crucial target in breast cancer therapy. The methodology included multiple stages: preparation of target proteins, preparation and screening of the metabolites, geometry optimization, molecular docking, and MD simulations. Results: The molecular docking simulations of 43 metabolites revealed three promising candidates: 2-Methyl (S35), benzeneethanol (S42), and 2,6-dimethyl-4-heptanone (S54), with binding affinities (ΔG) of -5.08, -5.06, and -4.90 kcal/mol, respectively. MD simulations further showed that the selected metabolites stabilized the ER-α-metabolite complex, with the 2,6-dimethyl-4-heptanone (S54) metabolite demonstrating the most negative total MM-GBSA energy value (ΔG = -22.98 kcal/mol), indicating a strong and stable binding interaction. Conclusion: 2,6-Dimethyl-4-heptanone, a metabolite from milk kefir, showed promising potential as a candidate for further development as a breast cancer treatment, offering a novel alternative to conventional therapies.

The molecular dynamics (MD) method was applied to investigate a chemical vapor deposition process on the ZSM-5(010) surface. Si(OH)4 molecules were placed on the ZSM-5(010) surface, and MD simulation was performed for 12 ps. We observed the formation and evaporation of H2O molecules over the ZSM-5(010) surface. It indicates that the surface chemical reactions such as Si(OH)4 + HO-[ZSM-5] → Si(OH)3−O-[ZSM-5] + H2O, Si(OH)3−O-[ZSM-5] + Si(OH)3−O-[ZSM-5] → [ZSM-5]-O−Si(OH)2−O−Si(OH)2−O-[ZSM-5] + H2O and others, take place during the MD simulation. The formation of new Si−O−Si bonds was also observed on the surface, indicating the crystal growth of the ZSM-5(010) surface. Moreover, the constructed SiO2 layer was not amorphous, but inherited the ZSM-5 structure, keeping the 10-membered ring and (010) oriented configuration. Hence, we confirmed that the MD method was effective for reproducing and investigating the chemical vapor deposition process on zeolite surfaces on an atomic scale.

A new method is proposed for performing constant-pH molecular dynamics (MD) simulations, that is, MD simulations where pH is one of the external thermodynamic parameters, like the temperature or the pressure. The protonation state of each titrable site in the solute is allowed to change during a molecular mechanics (MM) MD simulation, the new states being obtained from a combination of continuum electrostatics (CE) calculations and Monte Carlo (MC) simulation of protonation equilibrium. The coupling between the MM/MD and CE/MC algorithms is done in a way that ensures a proper Markov chain, sampling from the intended semigrand canonical distribution. This stochastic titration method is applied to succinic acid, aimed at illustrating the method and examining the choice of its adjustable parameters. The complete titration of succinic acid, using constant-pH MD simulations at different pH values, gives a clear picture of the coupling between the trans/gauche isomerization and the protonation process, making it possible to reconcile some apparently contradictory results of previous studies. The present constant-pH MD method is shown to require a moderate increase of computational cost when compared to the usual MD method.

A novel energy conversion based method for velocity correction in molecular dynamics simulations

Thermophysical properties of phase change material NaCl and KCl were calculated using molecular dynamics (MD) simulations and a recent EIM interatomic potential. Density, thermal expansion coefficient, specific heat capacity were computed using equilibrium MD (EMD) simulations. The results are very close to the experimental values. The thermal conductivity was computed using two non-equilibrium MD (NEMD) methods and the results were compared with the experimental data. They appear to be relatively reasonable. Binary NaCl/KCl systems have also been investigated. The specific heat capacity with different compositions are calculated. They are very close with recent experimental results.

A 3D grinding molecular dynamics (MD) simulation model of monocrystal silicon is established. The characteristics of MD serial program and the feasibility of parallel simulation are presented. An MD simulation parallel algorithm in which the domain is decomposed twice is developed. Parallel program is made and executed. From the viewpoint of the instantaneous distribution of at-oms, the mechanism of monocrystal silicon grinding process is analyzed. In addition, through the comparison of the results between the serial and the parallel simulations, it is proved that the results of the parallel simulation is reliable. From the viewpoint of simula-tion size and computation time, the parallel program has great advantage over the serial program. In conclusion, the parallel program is effective and can be used in MD simulations of the system with different sizes.

The molecular dynamics (MD) method is a promising approach toward elucidating the molecular mechanisms of intrinsically disordered regions (IDRs) of proteins and their fuzzy complexes. This mini-review introduces recent studies that apply MD simulations to investigate the molecular recognition of IDRs. Firstly, methodological issues by which MD simulations treat IDRs, such as developing force fields, treating periodic boundary conditions, and enhanced sampling approaches, are discussed. Then, several examples of the applications of MD to investigate molecular interactions of IDRs in terms of the two kinds of complex formations; coupled-folding and binding and fuzzy complex. MD simulations provide insight into the molecular mechanisms of these binding processes by sampling conformational ensembles of flexible IDRs. In particular, we focused on all-atom explicit-solvent MD simulations except for studies of higher-order assembly of IDRs. Recent advances in MD methods, and computational power make it possible to dissect the molecular details of realistic molecular systems involving the dynamic behavior of IDRs.

We combine molecular dynamics (MD) and Monte Carlo (MC) simulations to study the properties of gas molecules confined between two hard walls of a microchannel or nanochannel. The coupling between MD and MC simulations is introduced by performing MD near the boundaries for accuracy and MC in the bulk because of the low computational cost. We characterize the influence of different densities and molecule sizes on the equilibrium properties of the gas in the microchannel. The effect of the particle size on the simulation results is very small in the case of a dilute gas and increases with the density. The hybrid MD-MC simulation method is validated by comparing the results for density and temperature profiles with those of pure MD and pure MC simulations. These results compare well for pure MD and pure MC, as well as hybrid MD-MC, both in the bulk and near the boundaries, when hard-sphere interactions are used. When Lennard-Jones potentials are used to accurately model the interactions between the gas and wall molecules instead, the results of pure MD simulations differ significantly from the pure MC simulations near the boundaries, but the results of the hybrid method compare well with the pure MD results near the wall, and with the pure MC and pure MD results in the middle of the channel. The hybrid method also very accurately simulates the interface between the MD and MC simulation domains. Comparisons between MD, MC, and hybrid MD-MC computational costs are outlined. The speedup when using 50% of the domain for MD simulations and 50% for MC simulations is very small compared to pure MD simulations times, but this speedup increases drastically for more realistic situations where the region near the wall is small compared to the bulk region.