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 (DG water) and solvation free enthalpies in the apolar solvent hexane (DG hexane) is presented. For a validation set of 685 molecules the average unsigned error (AUE) between DG water values calculated using the ATB3.0 and experiment is 3.9 kJ•mol-1. The slope of the line of best fit is 1.00, the intercept-1.0 kJ•mol-1 and the R 2 0.90. For the more restricted set of 239 molecules used to validate OPLS3 (J. Chem. Theory Comput. 2016, 12, 281-296.) the AUE using the ATB3.0 is just 2.7 kJ•mol-1 and the R 2 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.

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.

Methyl-branched fatty acids are widespread in prokaryotic membranes. Although anteiso and iso branching (that is on the antepenultimate and penultimate carbons) and the presence of multiple methyl branches in the phytanoyl chain are known to modify the thermotropic behavior and enhance the fluidity of lipid bilayers, little is known about the effect of methyl branching on the structure of lipid bilayers. In this study, molecular dynamics simulations are used to examine systematically the impact of one or more methyl branches at different positions along the sn-1 palmitoyl chain on the structural properties of a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid bilayer. It is found that methyl branching reduces lipid condensation, decreases the bilayer thickness, and lowers chain ordering. Branching also results in the formation of kinks at the branching point, thereby enhancing the fluidity of lipid bilayers. Furthermore, this effect varies in a methyl-position-dependent fashion. In the case of polymethylated chains, the simulations suggest that if the gap between the methyl groups is sufficient (two or three carbons), the effects of the methyl branches are additive and equivalent to the combined effect of the corresponding monomethyl-branched lipids.

The effect of varying the emitter concentration on the structural properties of an archetypal phosphorescent blend consisting of 4,4'-bis(N-carbazolyl)biphenyl and tris(2-phenylpyridyl)iridium(III) has been investigated using nonequilibrium molecular dynamics (MD) simulations that mimic the process of vacuum deposition. By comparison with reflectometry measurements,w es howt hat the simulations provideanaccurate model of the average density of such films. The emitter molecules were found not to be evenly distributed throughout film, but rather they can form networks that providec harge and/or energy migration pathways, even at emitter concentrations as lowas% 5weight percent. At slightly higher concentrations,percolated networks form that span the entire system. While such networks would give improved charge transport, they could also lead to more non-radiative pathwaysf or the emissive state and ar esultant loss of efficiency.

Atomistic nonequilibrium molecular dynamics simulations have been used to model the induction of molecular orientation anisotropy within the emission layer of an organic light-emitting diode (OLED) formed by vapor deposition. Two emitter species were compared: racemic fac-tris(2-phenylpyridine)iridium(III) (Ir(ppy)) and trans-bis(2-phenylpyridine)(acetylacetonate)iridium(III) (Ir(ppy)(acac)). The simulations show that the molecular symmetry axes of both emitters preferentially align perpendicular to the surface during deposition. The molecular arrangement formed on deposition combined with consideration of the transition dipole moments provides insight into experimental reports that Ir(ppy) shows isotropic emission, while Ir(ppy)(acac) displays improved efficiency due to an apparent preferential alignment of the transition dipole vectors parallel to the substrate. The simulations indicate that this difference is not due to differences in the extent of emitter alignment, but rather differences in the direction of the transition dipoles within the two complexes.

The effect of varying the emitter concentration on the structural properties of an archetypal phosphorescent blend consisting of 4,4'-bis(N-carbazolyl)biphenyl and tris(2phenylpyridyl)iridium(III) has been investigated using nonequilibrium molecular dynamics (MD) simulations that mimic the process of vacuum deposition. By comparison with reflectometry measurements,w es howt hat the simulations provideanaccurate model of the average density of such films. The emitter molecules were found not to be evenly distributed throughout film, but rather they can form networks that providec harge and/or energy migration pathways, even at emitter concentrations as lowas% 5weight percent. At slightly higher concentrations,percolated networks form that span the entire system. While such networks would give improved charge transport, they could also lead to more non-radiative pathwaysf or the emissive state and ar esultant loss of efficiency. Figure 1. Chemical structures of CBP (left) and Ir(ppy) 3 (right).

Sterols and hopanoids have been suggested to reinforce membranes and protect against unfavorable environmental conditions. In particular, hopanoids are found in high concentrations in membranes of thermotolerant and thermophilic bacteria. However, the mechanism whereby sterols and hopanoids stabilize membranes at elevated temperatures is poorly understood. Here, the effect of temperature on the ordering of lipids in bilayers containing cholesterol or the hopanoids bacteriohopanetetrol and diplopterol was explored using molecular dynamics simulations. It is shown that cholesterol induces a high level of ordering over a wide range of temperatures. Bacteriohopanetetrol promotes order within the lipid tails but enhances fluid-like properties of the head groups at high temperatures. In contrast, diplopterol partitions in the midplane of the bilayer. This suggests that individual hopanoids fulfill distinct functions in membranes, with the ordering properties of bacteriohopanetetrol being particularly well suited to maintain the integrity of membranes at temperatures preferred by thermotolerant and thermophilic bacteria.

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.