Application Of Molecular Simulations Research Articles

Molecular simulations in drug delivery: Opportunities and challenges

Molecular simulations are promising tools for in silico design of drug delivery formulations, as they provide a prediction of formulation properties prior to synthesis thus minimizing the need for in vitro and in vivo experimentation. The detailed molecular insight obtained by these simulations is precious and often beyond the reach of sophisticated experimental facilities. Although initially limited to the prediction of single‐molecule behavior (e.g., drug orientation in a bilayer), gradual advances in computing speed and efficient simulation approaches have made it feasible to employ these methods for phenomena occurring at substantially large length and time scales (e.g., carrier‐drug complexation) with modest computational cost and resources. We present a nonmathematical review of molecular simulation methods and their applications in drug delivery, with special emphasis on the use of atomistic and coarse‐grained Monte Carlo (MC) and molecular dynamics (MD) methods and excluding the drug docking studies used in drug discovery. Current capabilities and problems associated with the use of these methods in the context of drug delivery are highlighted, along with a discussion of representative applications of molecular simulations in drug delivery. We conclude that while molecular simulations are expected to play a central role in the future of drug delivery field, we require a concerted effort of computational scientists, experimentalists, and industry personnel working on drug delivery to identify specific areas where these simulations can be especially useful.This article is categorized under: Structure and Mechanism > Computational Materials Science Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods Software > Molecular Modeling

The Determination of Shale Gas Absolute Adsorption Basing on Molecular Dynamics Simulation

The adsorption experimental isotherms developed for excess adsorption of supercritical gases with the appearance of a distinct maximum and quick decrease cannot be explained with the base of the classic adsorption theory developed for absolute adsorption. The key of describing the adsorption of supercritical gases with classical adsorption theory is the correct conversion of the quantity of absolute adsorption and excess adsorption. According to Gibbs definition of adsorption, accurate evaluation of the adsorbed phase density is the key of the correct conversion of the quantity of absolute adsorption and excess adsorption. Based on the principle of molecular dynamics and the application of molecular simulation, it simulates the density of supercritical methane under 0 to 50 MPa, and the calculation results are in accordance with National Institute of Standards and Technology (NIST) data. Based on this, combined with the single molecular adsorption theory, it puts forward a new method of conversion of the quantity of absolute adsorption and excess adsorption that can be applied to a great range of pressure. This method has higher accuracy, and breaks through the existing conversion methods with limit of low pressure conditions.

The right isotherms for the right reasons? Validation of generic force fields for prediction of methane adsorption in metal-organic frameworks

In recent years, the use of computational tools to aid in the evaluation, understanding and design of advanced porous materials for gas storage and separation processes has become evermore widespread. High-performance computing facilities have become more powerful and more accessible and molecular simulation of gas adsorption has become routine, often involving the use of a number of default and commonly used parameters as a result. In this work, we consider the application of molecular simulation in one particular field of adsorption – the prediction of methane adsorption in metal-organic frameworks in the low loading regime – and employ a range of computational techniques to evaluate the appropriateness of many commonly chosen simulation parameters to these systems. In addition to confirming the power of relatively simple generic force fields to quickly and accurately predict methane adsorption isotherms in a range of MOFs, we demonstrate that these force fields are capable of providing detailed molecular-level information which is in very good agreement with quantum chemical predictions. We highlight a number of chemical systems in which molecular-level insight from generic force fields should be approached with a degree of caution and provide some general recommendations for best practice in simulations of CH4 adsorption in MOFs.

A load-balancing workload distribution scheme for three-body interaction computation on Graphics Processing Units (GPU)

Three-body effects play an important role for obtaining quantitatively high accuracy in a variety of molecular simulation applications. However, evaluation of three-body potentials is computationally costly, generally of O(N3) where N is the number of particles in a system. In this paper, we present a load-balancing workload distribution scheme for calculating three-body interactions by taking advantage of the Graphics Processing Units (GPU) architectures. Perfect load-balancing is achieved if N is not divisible by 3 and nearly perfect load-balancing is obtained if N is divisible by 3. The workload distribution scheme is particularly suitable for the GPU’s Single Instruction Multiple Threads (SIMT) architecture, where particle’s data accessed by threads can be coalesced into efficient memory transactions. We use two potential energy functions with three-body terms, the Axilrod–Teller potential and the Context-based Secondary Structure Potential, as examples to demonstrate the effectiveness of our workload distribution scheme.

Force-Field Based Quasi-Chemical Method for Rapid Evaluation of Binary Phase Diagrams.

We present the Pair Configurations to Molecular Activity Coefficients (PAC-MAC) method. The method is based on the pair sampling technique of Blanco (Fan, C. F.; Olafson, B. D.; Blanco, M.; Hsu, S. L. Application of Molecular Simulation to Derive Phase Diagrams of Binary Mixtures. Macromolecules 1992, 25, 3667-3676) with an extension that takes the packing of the molecules into account by a free energy model. The intermolecular energy is calculated using classical force fields. PAC-MAC is able to predict activity coefficients and corresponding vapor-liquid equilibrium diagrams at least 4 orders of magnitude faster than molecular simulations. The accuracy of the PAC-MAC method is tested by comparing the results with experimental data and with the results of the COSMO-SAC model (Lin, S.-T.; Sandler, S. I. A Priori Phase Equilibrium Prediction from a Segment Contribution Solvation Model. Ind. Eng. Chem. Res. 2002, 41, 899-913). PAC-MAC (using the OPLS-aa force field) is shown to be comparable in accuracy to COSMO-SAC, at the considerable advantage that PAC-MAC in principle does not require quantum calculation, provided proper force fields to be available.

Multipolar Ewald methods, 2: applications using a quantum mechanical force field.

A fully quantum mechanical force field (QMFF) based on a modified “divide-and-conquer” (mDC) framework is applied to a series of molecular simulation applications, using a generalized Particle Mesh Ewald method extended to multipolar charge densities. Simulation results are presented for three example applications: liquid water, p-nitrophenylphosphate reactivity in solution, and crystalline N,N-dimethylglycine. Simulations of liquid water using a parametrized mDC model are compared to TIP3P and TIP4P/Ew water models and experiment. The mDC model is shown to be superior for cluster binding energies and generally comparable for bulk properties. Examination of the dissociative pathway for dephosphorylation of p-nitrophenylphosphate shows that the mDC method evaluated with the DFTB3/3OB and DFTB3/OPhyd semiempirical models bracket the experimental barrier, whereas DFTB2 and AM1/d-PhoT QM/MM simulations exhibit deficiencies in the barriers, the latter for which is related, in part, to the anomalous underestimation of the p-nitrophenylate leaving group pKa. Simulations of crystalline N,N-dimethylglycine are performed and the overall structure and atomic fluctuations are compared with the experiment and the general AMBER force field (GAFF). The QMFF, which was not parametrized for this application, was shown to be in better agreement with crystallographic data than GAFF. Our simulations highlight some of the application areas that may benefit from using new QMFFs, and they demonstrate progress toward the development of accurate QMFFs using the recently developed mDC framework.

Application of molecular simulations: Insight into liquid bridging and jetting phenomena

Molecular dynamics simulations have been performed on pure liquid water, aqueous solutions of sodium chloride, and polymer solutions exposed to a strong external electric field with the goal to gain molecular insight into the structural response to the field. Several simulation methodologies have been used to elucidate the molecular mechanisms of the processes leading to the formation of liquid bridges and jets (in the production of nanofibers). It is shown that in the established nanoscale structures, the molecules form a chain with their dipole moments oriented parallel to the applied field throughout the entire sample volume. The presence of ions may disturb this structure leading to its ultimate disintegration into droplets; the concentration dependence of the threshold field required to stabilize a liquid column has been determined. Conformational changes of the polymer in the jetting process have also been observed.

On the numerical treatment of dissipative particle dynamics and related systems

We review and compare numerical methods that simultaneously control temperature while preserving the momentum, a family of particle simulation methods commonly used for the modelling of complex fluids and polymers. The class of methods considered includes dissipative particle dynamics (DPD) as well as extended stochastic-dynamics models incorporating a generalized pairwise thermostat scheme in which stochastic forces are eliminated and the coefficient of dissipation is treated as an additional auxiliary variable subject to a feedback (kinetic energy) control mechanism. In the latter case, we consider the addition of a coupling of the auxiliary variable, as in the Nosé–Hoover–Langevin (NHL) method, with stochastic dynamics to ensure ergodicity, and find that the convergence of ensemble averages is substantially improved. To this end, splitting methods are developed and studied in terms of their thermodynamic accuracy, two-point correlation functions, and convergence. In terms of computational efficiency as measured by the ratio of thermodynamic accuracy to CPU time, we report significant advantages in simulation for the pairwise NHL method compared to popular alternative schemes (up to an 80% improvement), without degradation of convergence rate. The momentum-conserving thermostat technique described here provides a consistent hydrodynamic model in the low-friction regime, but it will also be of use in both equilibrium and nonequilibrium molecular simulation applications owing to its efficiency and simple numerical implementation.

Application of Molecular Simulation on Wettability and its Alteration

As the mechanical mechanism in interfacial phenomenon, interfacial forces are known as important but difficult to measure experimentally. In recent years, molecular simulation has been rapidly developed to give novel way in inter-molecular forces. In this study, molecular simulation is introduced into wettability and several formulas are presented to model forces and their microscopic effect among water, vapor and quartz phases. A novel dynamic method is proposed to determine the reasonable value of the cutoff distance to calculate the contact angles in vapor-water-quartz systems with and without fluorocarbon surfactants treated using molecular simulation. With other improvement in molecular simulation, the results of the contact angles are closely consistent with the measured data.

Adaptive Biasing Combined with Hamiltonian Replica Exchange to Improve Umbrella Sampling Free Energy Simulations

The calculation of binding free energies using potential of mean force based techniques is an important application of molecular simulations. Typically, a potential of mean force (PMF) along the separation distance between two binding molecules is calculated using umbrella sampling (US). Convergence can be improved by introducing restraints on the relative position and orientation of the molecules as well as on their configurational freedom. Application of such umbrella sampling protocol on DNA in complex with the minor-groove binding ligand furamidine failed to yield converged results within reasonable simulation time. Significant energy barriers and tightly bound water molecules in the DNA minor groove that only occasionally exchanged with the bulk appeared to be a major reason for insufficient convergence. However, convergence could be greatly improved by a combination of standard phase space reduction techniques with flattening of the free energy landscape and configurational exchanges using the Hamiltonian replica exchange method. The approach uses an iteratively adapting biasing potential that corresponds to a previously calculated PMF and smoothens the free energy surface in combination with replica exchanges along the reaction coordinate. In contrast to standard US, the combined method resulted in rapid convergence of calculated free energy changes along the separation distance coordinate and excellent agreement of dissociation and association calculations with experimental results.

Roadmaps through Free Energy Landscapes Calculated Using the Multidimensional vFEP Approach

The variational free energy profile (vFEP) method is extended to two dimensions and tested with molecular simulation applications. The proposed 2D-vFEP approach effectively addresses the two major obstacles to constructing free energy profiles from simulation data using traditional methods: the need for overlap in the re-weighting procedure and the problem of data representation. This is especially evident as these problems are shown to be more severe in two dimensions. The vFEP method is demonstrated to be highly robust and able to provide stable, analytic free energy profiles with only a paucity of sampled data. The analytic profiles can be analyzed with conventional search methods to easily identify stationary points (e.g. minima and first-order saddle points) as well as the pathways that connect these points. These "roadmaps" through the free energy surface are useful not only as a post-processing tool to characterize mechanisms, but can also serve as a basis from which to direct more focused "on-the-fly" sampling or adaptive force biasing. Test cases demonstrate that 2D-vFEP outperforms other methods in terms of the amount and sparsity of the data needed to construct stable, converged analytic free energy profiles. In a classic test case, the two dimensional free energy profile of the backbone torsion angles of alanine dipeptide, 2D-vFEP needs less than 1% of the original data set to reach a sampling accuracy of 0.5 kcal/mol in free energy shifts between windows. A new software tool for performing one and two dimensional vFEP calculations is herein described and made publicly available.

Atomistic simulation based prediction of the solvent effect on the molecular mobility and glass transition of poly (methyl methacrylate)

We present an investigation of the retained solvent effect on the glass transition temperature (Tg) of poly(methyl methacrylate) (PMMA) through all-atom molecular dynamics simulations. Addition of a weakly interactive solvent, tetrahydrofuran (THF), causes a depression of the PMMA Tg that can be identified through an analysis of the mean squared displacement of the polymer chains from atomistic trajectories. Our results are in very good agreement with an atomistically informed theoretical model based on free volume theory and demonstrate the applicability of molecular simulation to discern solvent effects on polymer thermomechanical behavior in silico.

Application of Molecular Simulations to CO2-Enhanced Oil Recovery: Phase Equilibria and Interfacial Phenomena

Summary Molecular simulation is a powerful technique for obtaining thermodynamic properties of a system of given composition at a specific temperature and pressure, and it enables us to visualize microscopic phenomena. In this work, we used simulations to study interfacial phenomena and phase equilibria, which are important to CO2-enhanced oil recovery (EOR). We conducted molecular dynamics (MD) simulation of an oil/water interface in the presence of CO2. It was found that CO2 was enriched at the interfacial region under all thermal conditions. Whereas the oil/water interfacial tension (IFT) increases with pressure, CO2 reduces the IFT by approximately one-third at low pressure and one-half at higher pressure. Further analysis on the basis of our MD trajectories shows that the O=C=O bonds to the water with a “T-shaped” structure, which provides the mechanism for CO2 enrichment at the oil/water interface. The residual nonnegligible IFT at high pressures implies that the connate or injected water in a reservoir strongly influences the transport of CO2/oil solutes in that reservoir. We used Gibbs ensemble Monte Carlo (GEMC) simulation to compute phase equilibria and obtain ternary phase diagrams of such systems as CO2/n-butane/N2 and CO2/n-butane/n-decane. Simulating hydrocarbon fluids with a mixture of CO2 and N2 enables us to evaluate the effects of N2 impurity on CO2-EOR. It also enables us to study the phase behavior, which is routinely used to evaluate the minimum miscibility pressure (MMP). We chose these two systems because experimental data are available for them. Our calculated phase equilibria are in fair agreement with experiments. We also discuss possible ways to improve the predictive capability for CO2/hydrocarbon systems. GEMC and MD simulations of systems with heavier hydrocarbons are straightforward and enable us to combine molecular-level thinking with process considerations in CO2-EOR.

Applicability of molecular simulations for modelling the adsorption of the greenhouse gas CF4 on carbons

Tetrafluoromethane, CF4, is a powerful greenhouse gas, and the possibility of storing it in microporous carbon has been widely studied. In this paper we show, for the first time, that the results of molecular simulations can be very helpful in the study of CF4 adsorption. Moreover, experimental data fit to the results collected from simulations. We explain the meaning of the empirical parameters of the supercritical Dubinin–Astakhov model proposed by Ozawa and finally the meaning of the parameter k of the empirical relation proposed by Amankwah and Schwarz.

Simulation of Solvent Extraction of South African Vitrinite- and Inertinite-Rich Coals

The application of molecular simulation and visualization approaches to solvent extraction was evaluated with large-scale molecular models (>14 000 atoms) of vitrinite- and inertinite-rich coals. A theoretical extraction yield was determined for the proposed molecular models using a molecule-specific solubility parameters approach. The theoretical extraction yields for these models agreed with the experimental trends. While this novel solubility estimation method did not predict the exact extraction yield of these models, there was agreement with extraction trends. Residue and extracted models were generated from the large-scale molecular coal models using solubility parameters and showed agreement with laser desorption−ionization time-of-flight mass spectrometry (LDTOF−MS) data. Thus, solvent extraction trends can be used to test the applicability of large-scale coal molecular models.

Ab initio electronic structure and direct dynamics simulations of CH3OCl

The ground (X1A′) and two lowest lying excited singlet states (11A″ and 21A′) of methyl hypochlorite have been examined using ab initio electronic structure techniques to validate computationally efficient methods, upon which direct dynamics can be based, versus high-level ones, for which direct dynamics would be intractable. Ground-state equilibrium geometries and vibrational frequencies determined using density functional theory (DFT) with the 6-31G(d) basis set are tested against coupled-cluster theory (CCSD(T)) results from the literature. Vertical excitation energies and transition dipole moments calculated at the complete active space self-consistent field CASSCF/6-31+G(d) level of theory are benchmarked against multireference configuration interaction (MRCI) results with the aug-cc-pVXZ (X = D, T, Q) family of basis sets. The excited-state gradients that will govern the classical dynamics are compared for CASSCF/6-31+G(d) versus MRCI/aug-cc-pVXZ (X = D, T). To carry out the ab initio molecular dynamics (AIMD), existing electronic structure codes have been interfaced with the molecular modelling toolkit (MMTK), an open-source program library for molecular simulation applications. We use two examples to demonstrate the use of direct dynamics in MMTK: a canonical ground-state trajectory to sample positions and momenta, and an excited-state microcanonical trajectory based on CASSCF. The work presented here forms the basis for future study of the photodissociation of CH3OCl. As well, the implementation of AIMD within MMTK provides a useful tool for examining a variety of other research problems.

Molecular simulation applied to fluid properties in the oil and gas industry

In order to illustrate the use of molecular simulation methods in the oil and gas industry, three typical fields of application are considered. The first of these is the prediction of fluid phase equilibria by Gibbs ensemble simulation, exemplified here by the systematic determination of full phase diagrams (including liquid–vapour critical points) for binary systems of hydrogen sulphide and various hydrocarbons (n-alkanes with 2–20 carbon atoms, benzene, ethylbenzene, cyclohexane). The second type of application is the adsorption equilibria in zeolites. For these applications, the comprehensive modelling of the interplay of hydrocarbon adsorption with polar compounds (alkanethiols, water) and cation mobility is a still a challenge for simulation methods. However encouraging results are shown when the different contributions to interaction energy (dispersion–repulsion, electrostatic, polarization) are separately addressed when simulating the adsorption of n-alkanes in sodium faujasites. The third field considered is the determination of transport properties, particularly viscosity, from equilibrium molecular dynamics (MD). Although they describe rather well the influence of pressure, temperature and carbon number, existing force fields for n-alkanes are found to underestimate the viscosity of liquids. By a specific modification of the torsion potential which does not alter the equilibrium conformations, the viscosity is significantly improved without compromising phase equilibrium properties. A brief outline of other current and future applications of molecular simulation in the oil and gas industry is given in conclusion.

UNDERSTANDING REACTIVE HAZARDS USING MOLECULAR SIMULATION: MECHANISMS OF HYDROXYLAMINE DECOMPOSITION

Reactive hazards have been a significant concern for the chemical process industries. Without sufficient control of chemical hazards and risks, reactive incidents have caused catastrophic consequences for humans and the environment worldwide. In order to help understand and evaluate reactive hazards, calorimetric investigations have been employed to characterize reactive chemical behavior. However, with the development of computer resources and computational chemistry, molecular simulation has become a powerful and reliable tool to complement and guide experimental testing. In this article, hydroxylamine (HA) calculations demonstrate the application of molecular simulation for understanding and controlling reactive hazards. Using the quantum mechanical software Gaussian 03, HA bimolecular or water-catalyzed HA isomerization to ammonia oxide in aqueous solution was identified as the most likely decomposition pathways. Based on these molecular simulation results, recommendations are provided for safer handling of HA.

Computer Simulation in Polymer Physical Chemistry and Its Application to Biomolecules

Applications of molecular simulation in the field of polymer physical chemistry are presented in terms of crystallization, interaction to small molecules, and hydration. Full atomistic models are suitable for investigating these phenomena since atomistic interaction plays important roles. From a different point of view, these studies in the field of polymer science lead to fundamental understandings of various biophysical problems, such as physical chemistry of amyloid fibrils, which may cause neurodegenerative diseases.

Methods and Applications of Molecular Simulation in Catalyst Research

The ab initio, semi-empirical, density functional theory (DFT) calculation methods of quantum mechanics, and the basic theories of molecule mechanics were discussed. The molecular dynamics (MD), Monte Carlo (MC) methods of molecular simulation and the commonly used hierarchical approach in catalyst research were reviewed. The applications of molecular simulations in catalyst study, such as simulations of adsorptions and diffusivities in zeolites, simulations of acquisitions of basis data, simulations of predictions of locations, and IR simulations of composite oxides, were introduced.