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The performance of organic optoelectronic devices, such as organic light-emitting diodes (OLEDs) and organic solar cells (OSCs), is intrinsically related to the molecular-scale morphology of the thin films from which they are composed. However, the experimental characterization of morphology at the molecular level is challenging due to the often amorphous or at best semicrystalline nature of these films. Classical molecular modeling techniques, such as molecular dynamics (MD) simulation, are increasingly used to understand the relationship between morphology and the properties of thin-film devices. PyThinFilm (github.com/ATB-UQ/PyThinFilm) is an open-source Python package which allows fully automated MD simulations of thin film growth to be performed using vacuum and/or solution deposition processes. PyThinFilm utilizes the GROMACS simulation package in combination with interaction parameters from the Automated Topology Builder (atb.uq.edu.au). Here, PyThinFilm is described along with an overview of applications in which PyThinFilm has been used to study the thin films of organic semiconductor materials typically used in OLEDs and OSCs.

The fusion of the viral and target cell membranes is a key step in the life cycle of all enveloped viruses. Here, a range of structural data is used to generate an evidence-based model of the active conformation of an archetypical type-I fusion protein, the Ebola glycoprotein 2 (GP2). The stability of the trimeric complex is demonstrated using molecular dynamics and validated by simulating the interaction of the complex with a lipid bilayer. In this model, the fusion peptides project away from the central helix bundle parallel to the target membrane. This maximizes contact with the host membrane, enhances lateral stability, and would explain why, when activated, viral fusion proteins are trimeric.

Molecular dynamics (MD) simulations were performed to investigate the dynamics of humic acid (HA) in an aqueous solution and the influence of pH, temperature, and HA concentration. The HA model employed in MD simulations was chosen and validated using experimental chemical composition data and Fourier transform infrared (FTIR) spectra. The simulations showed that the HA molecule has a strong propensity to adopt a compact conformation in water independent of pH, while the aggregation of HA was found to be pH-dependent. At high pH, the ionized HAs assembled into a thread-like structure, maximizing contact with water. At low pH, the neutral HAs formed a droplet-like aggregate, minimizing contact with the solvent. The simulation results are consistent with experimental data from dynamic light scattering (DLS) measurements and transmission electron microscopy (TEM) imaging. This work provides new insight into the folding and aggregation of HA as a function of pH and a molecular-level understanding of the relationship between the acidity and the structure, solubility, and aggregation of HA, with direct implications for HA-based remediation strategies of contaminated sites.

α-Helical membrane-active antimicrobial peptides (AMPs) are known to act via a range of mechanisms, including the formation of barrel-stave and toroidal pores and the micellisation of the membrane (carpet mechanism). Different mechanisms imply that the peptides adopt different 3D structures when bound at the water-membrane interface, a highly amphipathic environment. Here, an evolutionary algorithm is used to predict the 3D structure of a range of α-helical membrane-active AMPs at the water-membrane interface by optimising amphipathicity. This amphipathic structure prediction (ASP) is capable of distinguishing between curved and linear peptides solved experimentally, potentially allowing the activity and mechanism of action of different membrane-active AMPs to be predicted. The ASP algorithm is accessible via a web interface at http://atb.uq.edu.au/asp/.

Atomistic nonequilibrium molecular dynamics simulations have been used to model the orientation of a side-chain substituted dicyanovinyl oligothiophene, DCV4T-Et2, in thin films formed by vacuum deposition as used in organic photovoltaics. The orientation of the DCV4T-Et2 molecules was analyzed in neat layers deposited onto smooth or rough C60 substrates. The average angle between the long axis of DCV4T-Et2 and the horizontal was 21 +/- 1 degrees in the layer deposited on smooth C-60, in agreement with experimental measurements of layers deposited on silicon. In the layer deposited on rough C-60, the average angle was 25 +/- 2 degrees, which could lead to a decrease of 6% in the efficiency of light absorption compared to the layer on the smooth substrate. Thus, the simulations suggest that surface roughness must be considered in the design of model systems in order to maintain relevance to devices. Importantly, the simulations provide the ability to analyze the orientation of each individual molecule as opposed to experiments that provide an average across a film. The orientation of the thiophene rings of DCV4T-Et2 and the variation in orientation with respect to distance from the substrate were also analyzed and found to be similar for films on smooth and rough substrates. In addition, we show that X-ray diffraction patterns of the layers can be constructed from the simulations.

Emissive layers in phosphorescent organic light-emitting diodes commonly make use of guest-host blends such as Ir(ppy)

Computer simulations of molecular systems enable structure-energy-function relationships of molecular processes to be described at the sub-atomic, atomic, supra-atomic or supra-molecular level and plays an increasingly important role in chemistry, biology and physics. To interpret the results of such simulations appropriately, the degree of uncertainty and potential errors affecting the calculated properties must be considered. Uncertainty and errors arise from (1) assumptions underlying the molecular model, force field and simulation algorithms, (2) approximations implicit in the interatomic interaction function (force field), or when integrating the equations of motion, (3) the chosen values of the parameters that determine the accuracy of the approximations used, and (4) the nature of the system and the property of interest. In this overview, advantages and shortcomings of assumptions and approximations commonly used when simulating bio-molecular systems are considered. What the developers of bio-molecular force fields and simulation software can do to facilitate and broaden research involving bio-molecular simulations is also discussed.

The crucial role played by the solution-vapor interface in determining the growth and morphology of an organic semiconductor thin film formed by solvent evaporation has been examined in atomic detail. Specifically, how the loss of individual solvent molecules from the surface of the solution induces solute assembly has been studied using molecular dynamics simulations. The system consisted of

Warfarin, a widely used oral anticoagulant, is prescribed as a racemic mixture. Each enantiomer of neutral Warfarin can exist in 20 possible tautomeric states leading to complex pharmacokinetics and uncertainty as to the relevant species under different conditions. Here, the ability of alternative computational approaches to predict the preferred tautomeric form(s) of neutral Warfarin in different solvents is examined. It is shown that varying the method used to estimate the heat of formation in vacuum (direct or via homodesmic reactions), whether entropic corrections were included, and the method used to estimate the free enthalpy of solvation (i.e., PCM, COSMO, or SMD implicit models or explicit solvent) lead to large differences in the predicted rank and relative populations of the tautomers. In this case, only a combination of the enthalpy of formation using homodesmic reactions and explicit solvent to estimate the free enthalpy of solvation yielded results compatible with the available experimental data. The work also suggests that a small but significant subset of the possible Warfarin tautomers are likely to be physiologically relevant.

E-cadherin is a transmembrane glycoprotein that facilitates inter-cellular adhesion in the epithelium. The ectodomain of the native structure is comprised of five repeated immunoglobulin-like domains. All E-cadherin crystal structures show the protein in one of three alternative conformations: a monomer, a strand-swapped trans homodimer and the so-called X-dimer, which is proposed to be a kinetic intermediate to forming the strand-swapped trans homodimer. However, previous studies have indicated that even once the trans strand-swapped dimer is formed, the complex is highly dynamic and the E-cadherin monomers may reorient relative to each other. Here, molecular dynamics simulations have been used to investigate the stability and conformational flexibility of the human E-cadherin trans strand-swapped dimer. In four independent, 100 ns simulations, the dimer moved away from the starting structure and converged to a previously unreported structure, which we call the Y-dimer. The Y-dimer was present for over 90% of the combined simulation time, suggesting that it represents a stable conformation of the E-cadherin dimer in solution. The Y-dimer conformation is stabilised by interactions present in both the trans strand-swapped dimer and X-dimer crystal structures, as well as additional interactions not found in any E-cadherin dimer crystal structures. The Y-dimer represents a previously unreported, stable conformation of the human E-cadherin trans strand-swapped dimer and suggests that the available crystal structures do not fully capture the conformations that the human E-cadherin trans homodimer adopts in solution.

To enhance efficiency in molecular dynamics simulations, forces that vary slowly are often evaluated less often than those that vary rapidly. We show that the multiple-time-step algorithm implemented in recent versions of GROMACS results in significant differences in the collective properties of a system under conditions where the system was previously stable. The implications of changing the simulation algorithm without assessment of potential artifacts on the parametrization and transferability of effective force fields are discussed.

Based on differences between the x-ray crystal structures of ligand-bound and unbound forms, the activation of the erythropoietin receptor (EPOR) was initially proposed to involve a cross-action scissorlike motion. However, the validity of the motions involved in the scissorlike model has been recently challenged. Here, atomistic molecular dynamics simulations are used to examine the structure of the extracellular domain of the EPOR dimer in the presence and absence of erythropoietin and a series of agonistic or antagonistic mimetic peptides free in solution. The simulations suggest that in the absence of crystal packing effects, the EPOR chains in the different dimers adopt very similar conformations with no clear distinction between the agonist and antagonist-bound complexes. This questions whether the available x-ray crystal structures of EPOR truly represent active or inactive conformations. The study demonstrates the difficulty in using such structures to infer a mechanism of action, especially in the case of membrane receptors where just part of the structure has been considered in addition to potential confounding effects that arise from the comparison of structures in a crystal as opposed to a membrane environment. The work highlights the danger of assigning functional significance to small differences between structures of proteins bound to different ligands in a crystal environment without consideration of the effects of the crystal lattice and thermal motion.

A key factor in computational drug design is the consistency and reliability with which intermolecular interactions between a wide variety of molecules can be described. Here we present a procedure to efficiently, reliably and automatically assign partial atomic charges to atoms based on known distributions. We formally introduce the molecular charge assignment problem, where the task is to select a charge from a set of candidate charges for every atom of a given query molecule. Charges are accompanied by a score that depends on their observed frequency in similar neighbourhoods (chemical environments) in a database of previously parameterised molecules. The aim is to assign the charges such that the total charge equals a known target charge within a margin of error while maximizing the sum of the charge scores. We show that the problem is a variant of the well-studied multiple-choice knapsack problem and thus weakly \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\mathcal {NP}$$\end{document}NP-complete. We propose solutions based on Integer Linear Programming and a pseudo-polynomial time Dynamic Programming algorithm. We demonstrate that the results obtained for novel molecules not included in the database are comparable to the ones obtained performing explicit charge calculations while decreasing the time to determine partial charges for a molecule from hours or even days to below a second. Our software is openly available.

Biobutanol production by fermentation is potentially a sustainable alternative to butanol production from fossil fuels. However, the toxicity of butanol to fermentative bacteria, resulting largely from cell membrane fluidization, limits production titers and is a major factor limiting the uptake of the technology. Here, studies were undertaken, in vitro and in silico, on the butanol effects on a representative bacterial (i.e. Escherichia coli) inner cell membrane. A critical butanol : lipid ratio for stability of 2 : 1 was observed, computationally, consistent with complete interdigitation. However, at this ratio the bilayer was ∼20% thicker than for full interdigitation. Furthermore, butanol intercalation induced acyl chain bending and increased disorder, measured as a 27% lateral diffusivity increase experimentally in a supported lipid bilayer. There was also a monophasic Tm reduction in butanol-treated large unilamellar vesicles. Both behaviours are inconsistent with an interdigitated gel. Butanol thus causes only partial interdigitation at physiological temperatures, due to butanol accumulating at the phospholipid headgroups. Acyl tail disordering (i.e. splaying and bending) fills the subsequent voids. Finally, butanol short-circuits the bilayer and creates a coupled system where interdigitated and splayed phospholipids coexist. These findings will inform the design of strategies targeting bilayer stability for increasing biobutanol production titers. Ministry of Education (MOE) Nanyang Technological University National Research Foundation (NRF) Accepted version The computational work for this article was performed on resources of the National Supercomputing Centre, Singapore (https://www.nscc.sg). This work was supported by the Ministry of Education, Singapore (MOE) Grants M4360005 and Tier 1 RG146/17. SCELSE is funded by Singapore’s Ministry of Education, National Research Federation, Nanyang Technological University (NTU), and National University of Singapore (NUS) and hosted by NTU in partnership with NUS.

Emissive layers in phosphorescent organic light-emitting diodes commonly make use of guest–host blends such as Ir(ppy)3:CBP to achieve high external quantum efficiencies. However, while the Ir(ppy)3:CBP blend has been studied experimentally, crucial questions remain regarding how exciton diffusion is dependent on the distribution of the guest in the host, which can currently only be addressed at the atomic level via computational modeling. In this work, kinetic Monte Carlo simulations are utilized to gain insight into exciton diffusion in Ir(ppy)3:CBP blend films. The effects of both guest concentration and exciton density on various system properties are analyzed, including the probability of singlet excitons being converted to triplets, and the probability of those triplets decaying radiatively. Significantly, these simulations suggest that triplet diffusion occurs almost exclusively via guest–guest Dexter transfer and that concentration quenching of triplets induced by guest–guest intermolecular dipole-dipole interactions has a negligible effect at high exciton densities due to the prevalence of triplet–triplet annihilation. Furthermore, results for vacuum deposited morphologies derived from molecular dynamics simulations are compared to the results obtained using a simple cubic lattice approximation with randomly distributed guest molecules. We show that while differences in host-based processes such as singlet diffusion are observed, overall, the results on the fate of the excitons are in good agreement for the two morphology types, particularly for guest-based processes at low guest concentrations where guest clustering is limited.

Biological membranes display a great diversity in lipid composition and lateral structure that is crucial in a variety of cellular functions. Simulations of membranes have contributed significantly to the understanding of the properties, functions and behaviour of membranes and membrane-protein assemblies. This success relies on the ability of the force field used to describe lipid-lipid and lipid-environment interactions accurately, reproducibly and realistically. In this review, we present some recent progress in lipid force-field development and validation strategies. In particular, we highlight how a range of properties obtained from various experimental techniques on lipid bilayers and membranes, can be used to assess the quality of a force field. We discuss the limitations and assumptions that are inherent to both computational and experimental approaches and how these can influence the comparison between simulations and experimental data. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov.

The apparent activity of the multidrug transporter P-glycoprotein (P-gp) is enhanced by the presence of cholesterol. Whether this is due to the direct effect of cholesterol on the activity of P-gp, its effect on the local concentration of substrate in the membrane, or its effect on the rate of entry of the drug into the cell, is unknown. In this study, molecular dynamics simulation techniques coupled with potential of mean force calculations have been used to investigate the role of cholesterol in the movement of four P-gp substrates across a POPC bilayer in the presence or absence of 10% cholesterol. The simulations suggest that the presence of cholesterol lowers the free energy associated with entering the middle of the bilayer in a substrate-specific manner. These findings suggest that P-gp substrates may preferentially accumulate in cholesterol-rich regions of the membrane, which may explain its enhanced transport activity.

Free to read at publisher's site. Many venom peptides are potent and selective inhibitors of voltage-gated ion channels, including channels that are validated therapeutic targets for treatment of a wide range of human diseases. However, the development of novel venom-peptide-based therapeutics requires an understanding of their mechanism of action. In the case of voltage-gated ion channels, venom peptides act either as pore blockers that bind to the extracellular side of the channel pore or gating modifiers that bind to one or more of the membrane-embedded voltage sensor domains. In the case of gating modifiers, it has been debated whether the peptide must partition into the membrane to reach its binding site. In this study, we used surface plasmon resonance, fluorescence spectroscopy and molecular dynamics to directly compare the lipid-binding properties of two gating modifiers (μ-TRTX-Hd1a and ProTx-I) and two pore blockers (ShK and KIIIA). Only ProTx-I was found to bind to model membranes. Our results provide further evidence that the ability to insert into the lipid bilayer is not a requirement to be a gating modifier. In addition, we characterised the surface of ProTx-I that mediates its interaction with neutral and anionic phospholipid membranes and show that it preferentially interacts with anionic lipids.

The human multidrug transporter P-glycoprotein (P-gp) transports over 200 chemically diverse substrates, influencing their bioavailability and tissue distribution. Pharmacological studies have identified both competitive and noncompetitive P-gp substrates, but neither the precise location of the substrate binding sites, nor the basis of competitive and noncompetitive interactions has been fully characterized. Here, potential of mean force (PMF) calculations are used to identify the transport-competent minimum free energy binding locations of five compounds, Hoechst 33342, Rhodamine 123, paclitaxel, tariquidar, and verapamil to P-gp. Unrestrained molecular dynamics simulations were also performed to confirm the substrates were stable in the energy wells determined using the PMF calculations. All compounds had energy minima within the P-gp transmembrane (TM) pore. For Hoechst 33342 and Rhodamine 123, a second minimum outside the TM pore was also identified. Based on this and previous studies of nicardipine and morphine [ Subramanian et al. J. Chem. Inf. Model. 2015 , 55 , 1202 ], a general scheme that accounts for the observed noncompetitive and competitive substrate interactions with P-gp is proposed.

The ability of atomic interaction parameters generated using the Automated Topology Builder and Repository version 3.0 (ATB3.0) to predict experimental hydration free enthalpies (ΔGwater) and solvation free enthalpies in the apolar solvent hexane (ΔGhexane) is presented. For a validation set of 685 molecules the average unsigned error (AUE) between ΔGwater values calculated using the ATB3.0 and experiment is 3.8 kJ·mol-1. The slope of the line of best fit is 1.00, the intercept -1.0 kJ·mol-1, and the R2 0.90. For the more restricted set of 239 molecules used to validate OPLS3 (J. Chem. Theory Comput. 2016, 12, 281-296, DOI: 10.1021/acs.jctc.5b00864) the AUE using the ATB3.0 is just 2.7 kJ·mol-1 and the R2 0.93. A roadmap for further improvement of the ATB parameters is presented together with a discussion of the challenges of validating force fields against the available experimental data.

Molecular dynamics simulations and free energy calculations have been used to investigate the effect of ligand binding on the enantioselectivity of an epoxide hydrolase (EH) from Aspergillus niger. Despite sharing a common mechanism, a wide range of alternative mechanisms have been proposed to explain the origin of enantiomeric selectivity in EHs. By comparing the interactions of ( R)- and ( S)-glycidyl phenyl ether (GPE) with both the wild type (WT, E = 3) and a mutant showing enhanced enantioselectivity to GPE (LW202, E = 193), we have examined whether enantioselectivity is due to differences in the binding pose, the affinity for the ( R)- or ( S)- enantiomers, or a kinetic effect. The two enantiomers were easily accommodated within the binding pockets of the WT enzyme and LW202. Free energy calculations suggested that neither enzyme had a preference for a given enantiomer. The two substrates sampled a wide variety of conformations in the simulations with the sterically hindered and unhindered carbon atoms of the GPE epoxide ring both coming in close proximity to the nucleophilic aspartic acid residue. This suggests that alternative pathways could lead to the formation of a ( S)- and ( R)-diol product. Together, the calculations suggest that the enantioselectivity is due to kinetic rather than thermodynamic effects and that the assumption that one substrate results in one product when interpreting the available experimental data and deriving E-values may be inappropriate in the case of EHs.

Despite decades of research, the mechanism of action of the ABC multidrug transporter P-glycoprotein (P-gp) remains elusive. Due to experimental limitations, many researchers have turned to molecular dynamics simulation studies in order to investigate different aspects of P-gp function. However, such studies are challenging and caution is required when interpreting the results. P-gp is highly flexible and the time scale on which it can be simulated is limited. There is also uncertainty regarding the accuracy of the various crystal structures available, let alone the structure of the protein in a physiologically relevant environment. In this study, three alternative structural models of mouse P-gp (3G5U, 4KSB, 4M1M), all resolved to 3.8 Å, were used to initiate sets of simulations of P-gp in a membrane environment in order to determine: a) the sensitivity of the results to differences in the starting configuration; and b) the extent to which converged results could be expected on the times scales commonly simulated for this system. The simulations suggest that the arrangement of the nucleotide binding domains (NBDs) observed in the crystal structures is not stable in a membrane environment. In all simulations, the NBDs rapidly associated (within 10 ns) and changes within the transmembrane helices were observed. The secondary structure within the transmembrane domain was best preserved in the 4M1M model under the simulation conditions used. However, the extent to which replicate simulations diverged on a 100 to 200 ns timescale meant that it was not possible to draw definitive conclusions as to which structure overall was most stable, or to obtain converged and reliable results for any of the properties examined. The work brings into question the reliability of conclusions made in regard to the nature of specific interactions inferred from previous simulation studies on this system involving similar sampling times. It also highlights the need to demonstrate the statistical significance of any results obtained in simulations of large flexible proteins, especially where the initial structure is uncertain.