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Crystallographic studies of ligands bound to biological macromolecules (proteins and nucleic acids) represent an important source of information concerning drug-target interactions, providing atomic level insights into the physical chemistry of complex formation between macromolecules and ligands. Of the more than 115,000 entries extant in the Protein Data Bank (PDB) archive, ∼75% include at least one non-polymeric ligand. Ligand geometrical and stereochemical quality, the suitability of ligand models for in silico drug discovery and design, and the goodness-of-fit of ligand models to electron-density maps vary widely across the archive. We describe the proceedings and conclusions from the first Worldwide PDB/Cambridge Crystallographic Data Center/Drug Design Data Resource (wwPDB/CCDC/D3R) Ligand Validation Workshop held at the Research Collaboratory for Structural Bioinformatics at Rutgers University on July 30-31, 2015. Experts in protein crystallography from academe and industry came together with non-profit and for-profit software providers for crystallography and with experts in computational chemistry and data archiving to discuss and make recommendations on best practices, as framed by a series of questions central to structural studies of macromolecule-ligand complexes. What data concerning bound ligands should be archived in the PDB? How should the ligands be best represented? How should structural models of macromolecule-ligand complexes be validated? What supplementary information should accompany publications of structural studies of biological macromolecules? Consensus recommendations on best practices developed in response to each of these questions are provided, together with some details regarding implementation. Important issues addressed but not resolved at the workshop are also enumerated.

Solution-processing of organic light-emitting diode films has potential advantages in terms of cost and scalability over vacuum-deposition for large area applications. However, solution processed small molecule films can have lower overall device performance. Here, novel molecular dynamics techniques are developed to enable faster simulation of solvent evaporation that occurs during solution processing and give films of thicknesses relevant to real devices. All-atom molecular dynamics simulations are then used in combination with kinetic Monte Carlo transport modeling to examine how differences in morphology stemming from solution or vacuum film deposition affect charge transport and exciton dynamics in films consisting of light-emitting bis(2-phenylpyridine)(acetylacetonate)iridium(III) [Ir(ppy)2(acac)] guest molecules in a 4,4′-bis(N-carbazolyl)biphenyl host. While the structures of the films deposited from vacuum and solution were found to differ, critically, only minor variations in the transport properties were predicted by the simulations even if trapped solvent was present. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulations of the magainin MG-H2 peptide interacting with a model phospholipid membrane are used to investigate the mechanism by which antimicrobial peptides act. It is shown that in the simulations the pore is stabilized by a diffuse distribution of peptides, which bind to the rim of the pore, adopting a largely parallel orientation with respect to the plane of the membrane.

The phase behavior of a dipalmitoylphosphatidylcholine (DPPC)/palmitic acid (PA)/water 1:2:20 mixture is studied in atomic detail, using molecular dynamics simulations. Starting from a random solution of DPPC and PA in water, the system adopts a gel phase at temperatures below 330K or an inverted hexagonal phase above 330 K, and the direct transformation from a gel to an inverted hexagonal phase at 390K and a metastable fluid lamellar intermediate are observed.

The conformation on polymorphism behavior of the prion protein (PrP)106-126 peptide in different environments and conditions is studied by using various extensive molecular dynamic simulations. The results show an extended conformation adopted by the peptide in addition to the presence of helical structure in an apolar solvent.

The parameterization of a new coarse grained (CG) model for lipid and surfactant systems is presented. The results show the form of simulation should be used as much as possible to judge the quality of the CG force field in the application at hand.

Isothermal titration (micro)calorimetry and molecular dynamics simulation techniques are used to study the binding of a series of p-alkylbenzamidinium chloride inhibitors to the serine proteinase trypsin over a range of temperatures. The inhibitors show small differences in relative binding affinity but large compensating differences in enthalpy and entropy.

1,1,1-trifluoropropan-2-ol (TFIP) alcohol is used to study the influence of trifluoromethyl groups (CF3) on the physicochemical properties of fluorinated organic molecules. The difference in organization of hydration shell around the CF3 and CH3 groups helped in determining the trifluoromethanol and 1,1,1,3,3,3-hexafluropropano-2-ol.

The effect of the neglect of electronic polarization, on the relative stability of different conformations of a model peptide in a nonpolar environment, is investigated. The result reveals that the stability of confirmations which have an enhanced electric field, such as is generated by the formation of a helix dipole could significantly underestimated by the neglect of the effects of electronic polarization in weakly or nonpolar solvents.

The interaction of an interfacially activated enzyme, secretory phospholipase A2 (PLA2), with membranes containing spin labeled lipids is studied by EPR spectroscopy. It is found that under noncatalytic conditions, binding of PLA2 to fluid membranes causes the formation of a second, immobilized lipid component.

The conformational molecular dynamics of the flavin adenine dinucleotide (FAD) cofactor in aqueous solution are studied. The study shows that FAD displays a highly heterogeneous intensity decay, resulting in lifetime spectra with two major components.

A new model of 2,2,2-trifluoroethanol (TFE) suitable for condensed phase simulations is presented. The properties of the new model was compared with the available experimental data over a range of temperatures and the results indicate that the model reproduces the experimental properties of the neat liquid and of the mixtures with water.