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Permeability is a key property in various fields such as membrane technology for chemical separation and transport of substances through cell membranes. At the molecular scale, the counting method uses the number of membrane crossings in a conventional unbiased molecular dynamics simulation to predict the permeability. This contribution investigates under which conditions the counting method has insufficient statistics. An equation is derived for a compartmental model based on the inhomogeneous solubility–diffusion (Smoluchowski) model, giving insight into how the flux correlates with the solubility of permeants. This equation shows that a membrane crossing is a rare event not only when the membrane forms a large free energy barrier but also when the membrane forms a deep free energy well that traps permeants. Such a permeant trap has a high permeability; yet, the counting method suffers from poor statistics. To illustrate this, coarse-grained MD was run for 16 systems of dipalmitoylphosphatidylcholine bilayer membranes with different permeant types. The composition rule for permeability is shown to also hold for fluxes, and it is highlighted that the considered thickness of the membrane causes uncertainty in the permeability calculation of highly permeable membranes. In conclusion, a high permeability in itself is not an effective indicator of the sampling efficiency of the counting method, and caution should be taken for permeants whose solubility varies greatly over the simulation box. A practical consequence relevant in, e.g., drug design is that a drug with high membrane permeability might get trapped by membranes thus reducing its efficacy. [ABSTRACT FROM AUTHOR]

Permeation of many small molecules through lipid bilayers can be directly observed in molecular dynamics simulations on the nano- and microsecond timescale. While unbiased simulations provide an unobstructed view of the permeation process, their feasibility for computing permeability coefficients depends on various factors that differ for each permeant. The present work studies three small molecules for which unbiased simulations of permeation are feasible within less than a microsecond, one hydrophobic (oxygen), one hydrophilic (water), and one amphiphilic (ethanol). Permeabilities are computed using two approaches: counting methods and a maximum-likelihood estimation for the inhomogeneous solubility diffusion (ISD) model. Counting methods yield nearly model-free estimates of the permeability for all three permeants. While the ISD-based approach is reasonable for oxygen, it lacks precision for water due to insufficient sampling and results in misleading estimates for ethanol due to invalid model assumptions. It is also demonstrated that simulations using a Langevin thermostat with collision frequencies of 1/ps and 5/ps yield oxygen permeabilities and diffusion constants that are lower than those using Nosé–Hoover by statistically significant margins. In contrast, permeabilities from trajectories generated with Nosé–Hoover and the microcanonical ensemble do not show statistically significant differences. As molecular simulations become more affordable and accurate, calculation of permeability for an expanding range of molecules will be feasible using unbiased simulations. The present work summarizes theoretical underpinnings, identifies pitfalls, and develops best practices for such simulations. [ABSTRACT FROM AUTHOR]

This work aims at a critical assessmentof properties predictingor extracting information on the density and structure of liquids.State-of-the-art NVT and NpT molecular dynamics (MD) simulations havebeen performed on five liquids: methanol, chloroform, acetonitrile,tetrahydrofuran, and ethanol. These simulations allow the computationof properties based on first principles, including the equilibriumdensity and radial distribution functions (RDFs), characterizing theliquid structure. Refinements have been incorporated in the MD simulationsby taking into account basis set superposition errors (BSSE). An extendedBSSE model for an instantaneous evaluation of the BSSE correctionshas been proposed, and their impact on the liquid properties has beenassessed. If available, the theoretical RDFs have been compared withthe experimentally derived RDFs. For some liquids, significant discrepancieshave been observed, and a profound but critical investigation is presentedto unravel the origin of these deficiencies. This discussion is focusedon tetrahydrofuran where the experiment reveals some prominent peakscompletely missing in any MD simulation. Experiments providing informationon liquid structure consist mainly of neutron diffraction measurementsoffering total structure factors as the primary observables. The splittingof these factors in reciprocal space into intra- and intermolecularcontributions is extensively discussed, together with their sensitivityin reproducing correct RDFs in coordinate space. [ABSTRACT FROM AUTHOR]

Dimension reduction is often necessary when attempting to reach longer length and time scales in molecular simulations. It is realized by constraining degrees of freedom or by coarse-graining the system. When evaluating the accuracy of a dimensional reduction, there is a practical challenge: the models yield vectors with different lengths, making a comparison by calculating their dot product impossible. This article investigates mapping procedures for normal mode analysis. We first review a horizontal mapping procedure for the reduced Hessian techniques, which projects out degrees of freedom. We then design a vertical mapping procedure for the 'implosion' of the all-atom (AA) Hessian to a coarse-grained scale that is based upon vibrational subsystem analysis. This latter method derives both effective force constants and an effective kinetic tensor. Next, a series of metrics is presented for comparison across different scales, where special attention is given to proper mass-weighting. The dimension-dependent metrics, which require prior mapping for proper evaluation, are frequencies, overlap of normal mode vectors, probability similarity, Hessian similarity, collectivity of modes, and thermal fluctuations. The dimension-independent metrics are shape derivatives, elastic modulus, vibrational free energy differences, heat capacity, and projection on a predefined basis set. The power of these metrics to distinguish between reasonable and unreasonable models is tested on a toy alpha helix system and a globular protein; both are represented at several scales: the AA scale, a Gō-like model, a canonical elastic network model, and a network model with intentionally unphysical force constants. Published 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

An efficient protocol is presented to compensate for the basis set superposition error (BSSE) in DFT molecular dynamics (MD) simulations using localized Gaussian basis sets. We propose a classical correction term that can be added a posteriori to account for BSSE. It is tested to what extension this term will improve radial distribution functions (RDFs). The proposed term is pairwise between certain atoms in different molecules and was calibrated by fitting reference BSSE data points computed with the counterpoise method. It is verified that the proposed exponential decaying functional form of the model is valid. This work focuses on hydrogen-bonded liquids, i.e., methanol, and more specific on the intermolecular hydrogen bond, but in principle the method is generally applicable on any type of interaction where BSSE is significant. We evaluated the relative importance of the Grimme-dispersion versus BSSE and found that they are of the same order of magnitude, but with an opposite sign. Upon introduction of the correction, the relevant RDFs, obtained from MD, have amplitudes equal to experiment. [ABSTRACT FROM AUTHOR]

A new vibrational subsystem analysis (VSA) method is presented for coupling global motion to a local subsystem while including the inertial effects of the environment. The premise of the VSA method is a partitioning of a system into a smaller region of interest and a usually larger part referred to as environment. This method allows the investigation of local-global coupling, a more accurate estimation of vibrational free energy contribution for parts of a large system, and the elimination of the “tip effect” in elastic network model calculations. Additionally, the VSA method can be used as a probe of specific degrees of freedom that may contribute to free energy differences. The VSA approach can be employed in many ways, but it will likely be most useful for estimating activation free energies in QM/MM reaction path calculations. Four examples are presented to demonstrate the utility of this method. [ABSTRACT FROM AUTHOR]

The UiO-66 metal organic framework is one of the most thermally and chemically stable hybrid materials reported to date. However, it is also accepted that the material contains structurally embedded defects, which may be engineered to enhance properties towards specific applications such as catalysis, sensing, etc. The synthesis conditions determine to a large extent the level of perfection of the material and additionally the catalytic activity may be enhanced by post-synthesis activation at high temperature under vacuum, in which defect coordinating species (H2O, HCl, monocarboxylic modulators, etc.) evaporate. The molecular level characterization of defects is extremely challenging from both theoretical and experimental points of view. Such experimental endeavor was recently proposed via experimental SXRD measurements, also unraveling the coordination of water on the Zr–O–Zr defect sites [Angew. Chem., Int. Ed., 2015, 54, 11162–11167]. The present work provides a theoretical understanding of defect structures in UiO-66(Zr) by means of periodic density functional theory calculations and ab initio molecular dynamics simulations. A range of defect structures are generated with different numbers of missing linkers. For each of the defects, the free energetic and mechanical stability is discussed and the coordination of water and charge balancing hydroxide ions is studied. For catalysis applications, the material is mostly pretreated to remove water by dehydration reactions. For each of the proposed defect structures, mechanistic pathways for dehydration reactions of the Zr-bricks are determined employing nudged elastic band (NEB) calculations. During the dehydroxylation trajectory, loose hydroxyl groups and terephthalate decoordinations are observed. Furthermore, dehydration reactions are lower activated if terephthalate linkers are missing in the immediate environment of the inorganic brick. The creation of defects and the dehydration processes have a large impact on the mechanical properties of the material, which is evidenced by lower bulk moduli and elastic constants for structures with more defects. [ABSTRACT FROM AUTHOR]

The methanol-to-olefin process is a showcase example of complex zeolite-catalyzed chemistry. At real operating conditions, many factors affect the reactivity, such as framework flexibility, adsorption of various guest molecules, and competitive reaction pathways. In this study, the strength of first principle molecular dynamics techniques to capture this complexity is shown by means of two case studies. Firstly, the adsorption behavior of methanol and water in H-SAPO-34 at 350 °C is investigated. Hereby an important degree of framework flexibility and proton mobility was observed. Secondly, the methylation of benzene by methanol through a competitive direct and stepwise pathway in the AFI topology was studied. Both case studies clearly show that a first-principle molecular dynamics approach enables unprecedented insights into zeolite-catalyzed reactions at the nanometer scale to be obtained. [ABSTRACT FROM AUTHOR]

A Fourier-based method is presented to relate changes of the molecular structure during a molecular dynamics simulation with fluctuations in the electronic excitation energy. The method implies sampling of the ground state potential energy surface. Subsequently, the power spectrum of the velocities is compared with the power spectrum of the excitation energy computed using timedependent density functional theory. Peaks in both spectra are compared, and motions exhibiting a linear or quadratic behavior can be distinguished. The quadratically active motions are mainly responsible for the changes in the excitation energy and hence cause shifts between the dynamic and static values of the spectral property. Moreover, information about the potential energy surface of various excited states can be obtained. The procedure is illustrated with three case studies. The first electronic excitation is explored in detail and dominant vibrational motions responsible for changes in the excitation energy are identified for ethylene, biphenyl, and hexamethylbenzene. The proposed method is also extended to other low-energy excitations. Finally, the vibrational fingerprint of the excitation energy of a more complex molecule, in particular the azo dye ethyl orange in a water environment, is analyzed. [ABSTRACT FROM AUTHOR]

The free energy surface of zeolite ‐ catalyzed reactions at real operating conditions is typically complex. As such, techniques that allow sampling of larger portions of the potential and free energy landscape are required to mimic experimental conditions as closely as possible. Various points on the free energy surface can be connected by a multitude of reaction paths. Mapping the free energy surface by advanced molecular dynamics simulations of a zeolite ‐ catalyzed reaction can hence be compared with studying a map in an atlas to discover the possible means of transport to travel between two cities. For the complete story see the Full Paper on page 9385 by B. Ensing, V. Van Speybroeck et al. [ABSTRACT FROM AUTHOR]