Molecular Simulation Method Research Articles

A Study of the Mechanism of Binding between Neratinib and MAD2L1 Based on Molecular Simulation and Multi-spectroscopy Methods.

Nilatinib is an irreversible tyrosine kinase inhibitor, which is used in the treatment of some kinds of cancer. To study the interaction between Neratinib and MAD2L1, a potential tumor target, is of guiding significance for enriching the medicinal value of Neratinib. The binding mechanism between Mitotic arrest deficient 2-like protein 1 (MAD2L1) and Neratinib under simulative physiological conditions was investigated by molecule simulation and multi-spectroscopy approaches. Molecular docking showed the most possible binding mode of Neratinib-MAD2L1 and the potential binding sites and interaction forces of the interaction between MAD2L1 and Neratinib. Fluorescence spectroscopy experiments manifested that Neratinib could interact with MAD2L1 and form a complex by hydrogen bond and van der Waals interaction. These results were consistent with the conclusions obtained from molecular docking. In addition, according to Synchronous fluorescence and three-dimensional fluorescence results, Neratinib might lead to the conformational change of MAD2L1, which may affect the biological functions of MAD2L1. This study indicated that Neratinib could interact with MAD2L1 and lead to the conformational change of MAD2L1. These works provide helpful insights for the further study of biological function of MAD2L1 and novel pharmacological utility of Neratinib.

Modeling of Three-Dimensional RNA Structures Using SimRNA.

The molecules of the ribonucleic acid (RNA) perform a variety of vital roles in all living cells. Their biological function depends on their structure and dynamics, both of which are difficult to experimentally determine but can be theoretically inferred based on the RNA sequence. SimRNA is one of the computational methods for molecular simulations of RNA 3D structure formation. The method is based on a simplified (coarse-grained) representation of nucleotide chains, a statistically derived model of interactions (statistical potential), and the Monte Carlo method as a conformational sampling scheme.The current version of SimRNA (3.22) is able to predict basic topologies of RNA molecules with sizes up to about 50-70 nucleotides, based on their sequences only, and larger molecules if supplied with appropriate distance restraints. The user can specify various types of restraints, including secondary structure, pairwise atom-atom distances, and positions of atoms. SimRNA can be also used for studying systems composed of several chains of RNA. SimRNA is a folding simulations method, thus it allows for examining folding pathways, getting an approximate view of the energy landscapes.

Molecular simulation of energy storage of R1234yf, R1234ze(z), R32, and their mixtures in Co-MOF-74 materials

The heat capacity of working fluid can be enhanced through the mutual transformation between thermal energy and surface energy during the absorption and separation process of fluid molecules in porous materials. In this paper, molecular simulation (molecular dynamics and grand canonical Monte Carlo) methods were used to study the absorption and energy storage properties of R1234yf, R1234ze(z), R32 and their mixtures in Co-MOF-74. In order to evaluate the properties of thermal energy storage of metal organic heat carriers (MOHCs), the enthalpy difference (Δ h MOHCs) of MOHCs was calculated. Δ h MOHCs consists of the enthalpy of pure organic fluid (∆ h Fluid), the energy change of metal organic framework (MOF) nanoparticles (( ∫c p d T )MOFs) and the enthalpy of desorption (∆ h desorption). It can be inferred that MOHCs can strengthen the energy storage capacity of basic fluid when the sum of ( ∫c p d T )MOFs and ∆ h desorption is larger than ∆ h Fluid, and vice versa. For the purpose of calculating the energy change of metal organic framework nanoparticles (( ∫c p d T )MOFs), molecular dynamics simulation was adopted. Furthermore, grand canonical Monte Carlo methods were used to calculate the enthalpy of desorption (∆ h desorption). The results suggested that the adsorption amount of R32 in Co-MOF-74 is higher than that of R1234yf and R1234ze(z). The saturated adsorption pressure of R1234yf and R1234ze(z) is lower than that of R32. Besides, the saturated absorption amount of R1234ze(z) is higher than that of R1234yf. And the desorption heat of R32 is lower than that of R1234yf and R1234ze(z). As a result of phase transition, the enthalpy of organic fluid significantly increases at the temperature of phase transition. However, the enthalpy of phase transition of R32 is higher than that of R1234yf and R1234ze(z). The addition of Co-MOF-74 nanoparticles could enhance the energy storage capacity of the studied pure refrigerants. R1234yf and R1234ze(z) nanofluids have superior enhancement effect to that of R32 nanofluid. Nonetheless, the energy storage capacity of R32 nanofluid is depressed at the temperature of phase transition. This can be attributed to that the enthalpy of phase transition of R32 (∆ h Fluid) is higher than the sum of the energy of Co-MOF-74 nanoparticles (( ∫c p d T )MOFs) and the enthalpy of desorption (∆ h desorption) of R32 in Co-MOF-74. Moreover, due to the temperature of phase transition increases with the pressure increasing, the lowest point of energy storage enhancement appears at higher temperature. Besides, the absorption amount of R1234ze(z) and R1234yf is lower than that of R32 in the refrigerant mixture adsorption. What’s more, the absorption amount of R1234ze(z) in R1234ze(z)/R32 mixture is lower than that of R1234yf in R1234yf/R32 mixture. And this result is different from the adsorption of pure working fluid. Also, with the increase in temperature, the adsorption amount of R1234ze(z) and R1234yf shows a gradually increasing trend, while that of R32 gradually decreases. The desorption heat of R1234ze(z) and R1234yf is higher than that of R32 in the mixture adsorption. In general, this study is of great significance for theoretical analysis of adsorption characteristics of refrigerant molecules in porous media. And it can provide reliable basis for selecting appropriate refrigerant working mediums and MOFs to form optimal MOHCs in engineering.

Recent advances of pharmaceutical crystallization theories

Abstract As a technology of separation and purification, crystallization plays a vital role in diverse industries such as inorganic salt, pharmaceutical, and food industries, which has a huge impact on purity, crystal polymorph, crystal morphology, and particle size distribution of final products. In the past few decades, with the rapid advancement of experimental approaches and molecular simulation methods, considerable advances in the interpretation of crystallization mechanisms have been obtained, promoting the investigation and understanding of crystallization theories greatly. In this review, the advances of pharmaceutical crystallization theories in recent years from the perspectives of nucleation and crystal growth are summarized and discussed. Two thermodynamic models that are helpful in the study of the crystallization mechanisms will be introduced. In this section, the perturbed-chain statistical associating fluid theory (PC-SAFT) and a chemical-potential-gradient model will be introduced, which have been successfully applied in pharmaceutical solubility prediction, the research of dissolution mechanism as well as dissolution kinetics analysis. These two models are expected to be applied to the study of pharmaceutical crystallization process and mechanism. Furthermore, molecular simulation based on the interaction between particles can provide structural information, thermodynamics, and dynamics properties of complex systems at the molecular level, like intermolecular interaction and surface adsorption energies. Application and some shortcomings of molecular simulation, especially molecular dynamics simulation, in the field of pharmaceutical crystallization will be expounded.

First-Principles-Based Force Field for 2,6-Diamino-3,5-dinitropyrazine-1-oxide (LLM-105).

2,6-Diamino-3,5-dinitropyrazine-1-oxide (LLM-105) is a highly promising energetic material (EM) with high safety. Understanding its microscopic response mechanisms within the external stimulus is meaningful for the design of EMs. In order to comprehend the complicated phenomena, it is necessary to employ molecular simulation methods to investigate the response mechanisms with the force field (FF) at an atomic level. In this work, we developed a tailored FF for LLM-105 based on first-principles calculations. The validity of the FF was evaluated by molecular dynamics simulations. The structural parameters of LLM-105 predicted by FF are in good agreement with the experimental values, such as lattice constant, bond length, bond angle, dihedral angle and center of mass, and so forth. Moreover, the FF possesses good performance to describe the structural response on pressure accurately. In general, our work not only builds a balanced FF in gas and condensed phases, but also provides a useful tool to study the properties about LLM-105 at a large scale, which is helpful to improve the understanding about the balance between energy and safety in EMs.

Water-soluble complexes of orange pigments from Monascus sp. with HP-β-CD: Preparation, inclusion mechanism, and improved stability

Monascus pigments (Mps) have been utilized as natural food colourants in Asia for centuries. However, the poor water-solubility and photo-instability greatly restrict their applications in food industry. As a kind of orange Mps, monascorubrin (denoted as O1) is easy to react with substances containing amino groups (named amination reactions) and turn to red colour consequently. In this study, to maintain the original colour, solid inclusion complexes of O1 with hydroxypropyl-β-cyclodextrin (HP-β-CD) were prepared using freeze-drying method, and then investigated by SEM, FT-IR, PXRD, 1HNMR as well as molecular simulation method. Obtained results indicated that water solubility of O1 is significantly improved and its orange colour is successfully maintained at pH 3.5–9.0 upon complexation with HP-β-CD. Structural analysis suggested that O1 is encapsulated into the cavity of HP-β-CD, probably preventing it from amination reactions. Moreover, the pH and photo stability of Mps are markedly enhanced by complexation. This study provides an effective method for preparing water-soluble orange Mps that might be applicable in the beverage industry.

The tectonic stress–driving alteration and evolution of chemical structure for low- to medium-rank coals—by molecular simulation method

Coal organic macromolecular structure can be significantly altered by tectonic stress, but such macromolecular models are seldom reported. Here, based on the ultimate analysis, FT-IR, XPS, and 13C NMR results, three molecular models of primary coal (P1) and TDCs (the brittle coal model B2 and ductile coal model D3) within periodic boundary conditions were constructed through the molecular mechanics (MM) and molecular dynamics (MD) calculation methods. By comparing the morphology characteristics of the above three models, the crystal parameters decrease with the increasing deformation intensity, which leads to a tighter configuration. Bridge bonds are easier to be stretched and even broken up within deformed coal, which can furtherly crack the coal molecules into several smaller segments. Oxygen functional groups and methyl can be lost by the deformation on coal, which leads to an increase of the disorder units within coal molecules. On the one hand, the ductile deformation increases the condensation degree of the aromatic layers through promoting the small disorder units (viz. CO) embed into the secondary structural defects. On the other hand, it can also improve the order degree and the stacking degree of aromatic layers. By comparative analysis, the evolution path of tectonically deformed coal molecules is furtherly proposed. The ultra micropore volumes of three models are several orders of magnitude larger than the pore volume within the range of 2–50 nm, indicating that ultra micropores are important storage spaces for excess methane resulting in coal and gas outburst.

Absolute Adsorption of CH4 on Shale with the Simplified Local-Density Theory

Summary Using a thermogravimetric (TGA) method, the excess methane (CH4) adsorption of four organic shale samples is measured at temperatures of 303.15 to 383.15 K and pressures of 0 to 15.0 MPa. Simplified-local-density (SLD) theory is used to calculate the density distribution of CH4 in nanopores, which is then used to obtain the adsorbed CH4 density on four shale samples. Such density is applied to obtain the absolute CH4 adsorption by correcting the measured excess CH4 adsorption. SLD theory shows that the adsorbed CH4 density is strongly affected by temperature and pressure, as well as the pore size, which is in line with the previous findings from molecular simulations. SLD theory captures the density of the adsorbed phase of CH4 in the presence of CH4/pore-wall interactions. However, the SLD theory is more efficient than molecular simulation methods in determining the adsorbed CH4 density considering that only two parameters in the SLD model are adjusted to match the excess adsorption of CH4 on shale. It is observed that the corresponding absolute adsorption of CH4 is higher than the excess adsorption; this suggests that it is not reasonable to use the measured excess adsorption to estimate the storage of CH4 on shale. This study applies the SLD theory to investigate the adsorption behavior of CH4 in organic pores at different pressure/temperature conditions, and, more importantly, it yields a more-efficient approach (i.e., SLD theory) in determining the absolute adsorption than the sophisticated molecular simulations tools.

Curvature as a Collective Coordinate in Enhanced Sampling Membrane Simulations.

The plasticity of membranes plays an important functional role in cells, cell components, and micelles, where bending, budding, and remodeling implement numerous recognition and communication processes. Comparatively, molecular simulation methods to induce, control, and quantitatively characterize such deformations remain scarce. This work defines a novel collective coordinate associated with membrane bending, which strives to combine realism (by preserving the notion of local atomic curvatures) and low computational cost (allowing its evaluation at every time step of a molecular dynamics simulation). Enhanced sampling simulations along this conformational coordinate provide convenient access to the underlying bending free energy landscape. To showcase its potential, the method is applied to three state-of-the-art problems: the determination of the bending free energy landscape of a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) bilayer, the formation of a POPE liposome, and the study of the influence of the Pseudomonas quinolone signal on the budding of Gram-negative bacterial outer membranes.

Investigation of the factors influencing methane adsorption on illite

AbstractThe molecular simulation method was used to investigate the adsorption behaviors of methane on illite. The effects of several factors on methane adsorption, free gas amounts, and the proportions of absorbed gas in the illite nanopores, including the pore size, temperature, and water content, are discussed. The results obtained show that methane adsorption in illite nanopores is due mainly to van der Waals adsorption. With an increase in the pressure or of the pore size, the free gas amounts of methane increase, whereas the free gas amounts decrease with increasing temperature or water content. With increasing pressures or decreasing pore sizes, the methane adsorption capacity of the illite pores increases. When the pressure or pore size increases, the proportion of the adsorbed gas in the pores decreases. As the temperature increases, the methane adsorption capacity of the illite pores decreases, and the proportion of adsorbed gas in the illite pores decreases slightly. The adsorbed phase density decreases with increasing pore size and temperature, whereas the adsorbed phase density increases with increasing pressure. The electrostatic forces and hydrogen bonds have a positive effect on water adsorption in the illite nanopores, while the van der Waals forces have the opposite effect, which causes the water molecules in the illite pores to exist in the form of aggregates. The water molecules occupy the areas near the pore walls in a directional manner and occupy the adsorption space and the adsorption sites of methane, resulting in a decrease in the methane adsorption capacity and a slight reduction in the proportion of adsorbed gas.

Influencing factors for vulcanization induction period of accelerator / natural rubber composites: Molecular simulation and experimental study

Sulfonamide accelerators are one of the most widely used additives in rubber composites since they can significantly improve the rate of vulcanization process. However, usually the vulcanization induction period of the composites containing sulfonamide accelerators maybe too short, which leads to great potential safety hazards during manufacture process. Combining with experimental and molecular simulation methods, factors affecting the vulcanization induction period could be subdivided into the following items, i.e., the reactivity, the alkalinity, the solubility, the mobility and binding energy of accelerator in rubber composites. It was found that the chemical reactivity of accelerator is the key factor to affect the vulcanization induction period, and the well-dispersion and stability of accelerator in natural rubber could promote the vulcanization induction period reaction. This work may help us better understand the vulcanization induction period influencing factors from a micro-level perspective, and attempts to provide a guidance for screening and design of the new sulfonamide accelerators.

Simulation of low-pressure rf plasma treatment of ultrahigh molecular weight polyethylene

Methods of molecular dynamic simulation of the bombardment of polymeric materials by low-energy (up to 100 eV) ions generated in radio-frequency low-pressure (13.3-133 Pa) plasma are discussed. A model of RF plasma treatment of ultrahigh molecular weight polyethylene (UHMWPE) has been developed. It has been established that the bombardment of UHMWPE by argon ions initiates the fast rotation of the polymer chains, and the rupture of intramolecular bonds.

Theoretical Study of Structural and Spatial Properties of Kerogen

In this study, the structural information and spatial properties of the Longkou kerogen model were obtained by using molecular simulation methods. The density evaluation of the molecular model was carried out to investigate the morphological properties of internal pore structures that are limited or constrained by kerogen density. The density of the lowest-energy kerogen model is 1.01 g/cm3, which is consistent with its experimental value and close to the reference value for Green River Shale kerogen. Radial distribution function analysis indicated that the carbon skeleton of kerogen consists of significant amounts of sp2- and sp3-hybridized carbons. To further investigate the distribution characteristics of internal pore structures and provide valuable insights into the microstructures of the kerogen model, the morphology of pore volumes was created using Connolly surfaces. Meanwhile, a simplified mechanism model of kerogen pyrolysis was proposed based on the Mayer bond order analysis, which provided a strategy to accurately, quickly predict the cleavage behavior in the intrinsic structure of kerogen. This present study reveals inherent chemical features of kerogen and will aid in understanding the microscopic morphology characteristics of the pore network inside kerogen at the molecular level.

Applications of Molecular Simulation in the Discovery of Antituberculosis Drugs: A Review.

After decades of efforts, tuberculosis has been well controlled in most places. The existing drugs are no longer sufficient for the treatment of drug-resistant Mycobacterium tuberculosis due to significant toxicity and selective pressure, especially for XDR-TB. In order to accelerate the development of high-efficiency, low-toxic antituberculosis drugs, it is particularly important to use Computer Aided Drug Design (CADD) for rational drug design. Here, we systematically reviewed the specific role of molecular simulation in the discovery of new antituberculosis drugs. The purpose of this review is to overview current applications of molecular simulation methods in the discovery of antituberculosis drugs. Furthermore, the unique advantages of molecular simulation was discussed in revealing the mechanism of drug resistance. The comprehensive use of different molecular simulation methods will help reveal the mechanism of drug resistance and improve the efficiency of rational drug design. With the help of molecular simulation methods such as QM/MM method, the mechanisms of biochemical reactions catalyzed by enzymes at atomic level in Mycobacterium tuberculosis has been deeply analyzed. QSAR and virtual screening both accelerate the development of highefficiency, low-toxic potential antituberculosis drugs. Improving the accuracy of existing algorithms and developing more efficient new methods for CADD will always be a hot topic in the future. It is of great value to utilize molecular dynamics simulation to investigate complex systems that cannot be studied in experiments, especially for drug resistance of Mycobacterium tuberculosis.

CO2/N2 switchable aqueous foam stabilized by SDS/C12A surfactants: Experimental and molecular simulation studies

A novel CO2/N2 switchable aqueous foam was developed using a CO2-responsive surfactant N,N-dimethyl-N-dodecyl amine (C12A) and a conventional surfactant sodium dodecyl sulfate (SDS). The performance and mechanism of this switchable foam were studied by both experiment and molecular simulation methods. Experimental results demonstrate that the foam stabilized by SDS/C12A surfactants has better stability and water carrying capacity than single C12A foam. The foam could be rapidly switched between stable and unstable states at ambient temperature with CO2 or N2 as the triggers. Simulation results shows that when CO2 was introduced, most of SDS and C12A molecules aggregated in the water phase, instead of adsorbing at the air-water interface to stabilize the foam films. The strong electrostatic attraction between protonated C12A and SDS molecules could account for the aggregation. Due to the presence of limited surfactants located at the air-water interface after introducing CO2, the foam bursts quickly.

Study on mechanism and method of membrane preparation and membrane process optimization based on molecular structure analysis of noneffective common macromolecules

The molecular weight of the effective components of traditional Chinese medicine( TCM) is usually less than 1 000.However, " noneffective common macromolecules"( starch,pectin and other macromolecules commonly present in the water extract of TCM) generally have no physiological activity,which restricts the overall advantages of membrane technology to obtain small molecular pharmacodynamic substances,and such macromolecules are the main influence factor of membrane fouling. Therefore,in order to obtain the total pharmacological efficacy of TCM,based on the molecular structure analysis of noneffective common macromolecules,aimed at the key scientific problems in correlation between the molecular structure of noneffective common macromolecules and the pore structure of membrane material,and by referring to the material science theory and molecular simulation method,the correlations between noneffective common macromolecules' molecular structure-solution environment-membrane antagonism were investigated. Multidisciplinary approaches could be integrated to: ① optimize the spatial form of membrane surface and improve the membrane's antifouling ability; ② accurately control the pore structure and the size distribution of membranes,aimed at the innovative preparation technology of special membrane used for TCM; ③ adjust solution environment based on the analysis of molecular structure,and establish the pretreatment method based on the optimization of solution environment. Furthermore,the technical bottleneck on how to obtain the pharmacodynamic micromolecules effectively might be solved,and the theory and technology about TCM pharmaceutical engineering could be developed based on the concept of multivariate and integration.

Extension of the SAFT-VR-Mie equation of state for adsorption

An empirical extension of the Statistical Associating Fluid Theory (SAFT-VR-Mie) is presented to take into account the effect of confinement of fluids within cylindrical nanopores. The modification of the equation of state retains the bulk phase limit presented in the original formulation and adds a term corresponding to the contribution to the Helmholtz energy of the confined fluid. The resulting expression employs the fluid-fluid parameters obtained from fitting bulk fluid behaviour and adds two additional adjustable parameters reflecting the strength of the solid-fluid energy and the range of the surface attraction. The capability of the theoretical model is showcased by fitting adsorption isotherms of methane and n −nonane on activated carbons; ethane, n −hexane and benzene on MCM-41, and methane and carbon dioxide on carbon surrogate models of shale rocks; providing for an accurate correlation of the data with parameters that are temperature-independent and robust. The physical nature of the underlying model allows it to be mapped to fluid-solid molecular models which can then be resolved employing classical molecular simulation methods, providing for an avenue into probing not only the adsorption behaviour but also the transport and interfacial properties.

The Study of Release Mechanisms for Drug in Cyclodextrin Metal-Organic Frameworks.

γ-Cyclodextrin metal–organic frameworks (γCDMOF) recently emerged as biofriendly, highly porous, and crystalline materials with potential applications in drug delivery. However, little is known about their drug entrapment and release characteristics, which are key parameters in the design of drug carriers. The macroscopic properties of a material are determined by its microstructure. Thus, the characteristics of the constitutive units of the cubic crystalline γCDMOF determine their drug loading and release behaviors. In this study, the release profile of prednisolone (PNS) form γCDMOF was predicted, and the mechanism was analyzed based on the γCDMOF molecular structure. For the first time, experimental, molecular simulation, and mathematical modeling methods were combined to gain insights into the drug distribution in cubic porous crystals of γCDMOF as well as on drug release kinetics. The predicted release profile was in good agreement with the experimental results, showing that the modeling method was reliable. The methodology developed here could provide a reference for further investigations of drug penetration and release in supramolecular systems.

Enhancing Biomolecular Sampling with Reinforcement Learning: A Tree Search Molecular Dynamics Simulation Method.

This paper proposes a novel molecular simulation method, called tree search molecular dynamics (TS-MD), to accelerate the sampling of conformational transition pathways, which require considerable computation. In TS-MD, a tree search algorithm, called upper confidence bounds for trees, which is a type of reinforcement learning algorithm, is applied to sample the transition pathway. By learning from the results of the previous simulations, TS-MD efficiently searches conformational space and avoids being trapped in local stable structures. TS-MD exhibits better performance than parallel cascade selection molecular dynamics, which is one of the state-of-the-art methods, for the folding of miniproteins, Chignolin and Trp-cage, in explicit water.

Multiscale investigation of Kolmogorov flow: From microscopic molecular motions to macroscopic coherent structures

It is extremely expensive to study turbulence using conventional molecular simulation methods such as direct simulation Monte Carlo and molecular dynamics methods, as the molecular scales and the turbulent characteristic scales are significantly separated. To bridge this gap, we employ a particle Fokker-Planck method, namely, the Langevin dynamics simulation method, to study two-dimensional Kolmogorov flow, which is induced by a spatially periodic external force in an unbounded domain. Our simulation results predict that when the Reynolds number (Re) exceeds the critical value, a sequence of bifurcations takes place in the flow as the Reynolds number increases, forming a variety of flow patterns. Correspondingly, the effective diffusion coefficient is enhanced due to convection. Two main regimes of the flow have been observed: the small-scale cellular structure regime (Rec < Re < 8Rec), and the large-scale coherent structure regime (Re > 8Rec). We demonstrate that Langevin dynamics can capture the double kinetic-energy cascade when the large-scale structure is formed in two-dimensional turbulence: the inverse energy cascade has a scaling law of k−4 due to energy condensation in the large-scale structures, while the direct energy cascade has an exponential decay corresponding to the dissipation mechanism. This work provides strong evidence that Langevin dynamics is a promising multiscale tool to study turbulence from molecular motions to large-scale coherent structures.