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Alternation in various properties of n-alkanes (CnH2n+2) as a function of carbon content (n) is termed odd-even effect. Here, we report a comprehensive molecular dynamics simulation study on n-alkane systems carried out with n ranging between 3 (propane) and 8 (octane), examining the odd-even effect in melting point, density, intramolecular conformational ordering, translational and rotational motion. We observe an odd-even alternation in these properties, but with heptane (n = 7) exhibiting anomalous behavior for all except conformational ordering. Our simulations also show the presence of odd-even behavior in rotational and translational dynamics, below and above the melting point, respectively. The results highlight the role of both molecular shape and the variation in density and their interplay in the origins of the odd-even effect., 22 pages, first 16 constituting the main, followed by 6 more of supplementary material. 5 figures and 1 Table in the main, 6 figures and 1 Table in the supplementary material

Many measurements on soft condensed matter (e.g., biological and materials) systems track low-dimensional observables projected from the full system phase space as a function of time. Examples are dynamic structure factors, spectroscopic and rheological response functions, and time series of distances derived from optical tweezers, single-molecule spectroscopy and molecular dynamics simulations. In many such systems the projection renders the reduced dynamics non-Markovian and the observable is not prepared in, or initially sampled from and averaged over, a stationary distribution. We prove that such systems always exhibit non-equilibrium, time asymmetric dynamics. That is, they evolve in time with a broken time-translation invariance in a manner closely resembling aging dynamics. We identify the entropy associated with the breaking of time-translation symmetry that is a measure of the instantaneous thermodynamic displacement of latent, hidden degrees of freedom from their stationary state. Dynamical time asymmetry is a general phenomenon, independent of the underlying energy surface, and is frequently even visible in measurements on systems that have fully reached equilibrium. This finding has fundamental implications for the interpretation of many experiments on, and simulations of, biological and materials systems.

The reliable prediction of the affinity of candidate peptides for the major histocompatibility complex (MHC) is important for predicting their potential antigenicity, and thus influences medical applications, such as decisions on their inclusion in T cell-based vaccines. Here, we present a rapid, predictive computational approach that combines a popular, sequence-based artificial neural network method, NetMHCpan 4.0, with 3D structural modeling. We find that the ensembles of bound peptide conformations generated by the programs MODELLER and Rosetta FlexPepDock are less variable in geometry for strong binders than for low-affinity peptides. In tests on 1,271 peptide sequences for which the experimental dissociation constants for binding to the well-characterized murine MHC allele, H-2D(b) are known, by applying thresholds for geometric fluctuations the structure-based approach in a stand-alone manner drastically improves the statistical specificity, reducing the number of false positives. Furthermore, filtering candidates generated with NetMHCpan 4.0 with the structure-based predictor led to an increase in the positive predictive value (PPV) of the peptides correctly predicted to bind very strongly (i.e., k(D)

Ensemble docking corresponds to the generation of an "ensemble" of drug target conformations in computational structure-based drug discovery, often obtained by using molecular dynamics simulation, that is used in docking candidate ligands. This approach is now well established in the field of early-stage drug discovery. This review gives a historical account of the development of ensemble docking and discusses some pertinent methodological advances in conformational sampling.

This paper describes and illustrates the use of ensemble-based docking, i.e., using a collection of protein structures in docking calculations for hit discovery, the exploration of biochemical pathways and toxicity prediction of drug candidates. We describe the computational engineering work necessary to enable large ensemble docking campaigns on supercomputers. We show examples where ensemble-based docking has significantly increased the number and the diversity of validated drug candidates. Finally, we illustrate how ensemble-based docking can be extended beyond hit discovery and toward providing a structural basis for the prediction of metabolism and off-target binding relevant to pre-clinical and clinical trials.

A cellulose synthesis complex with a "rosette" shape is responsible for synthesis of cellulose chains and their assembly into microfibrils within the cell walls of land plants and their charophyte algal progenitors. The number of cellulose synthase proteins in this large multisubunit transmembrane protein complex and the number of cellulose chains in a microfibril have been debated for many years. This work reports a low resolution structure of the catalytic domain of CESA1 from Arabidopsis (Arabidopsis thaliana; AtCESA1CatD) determined by small-angle scattering techniques and provides the first experimental evidence for the self-assembly of CESA into a stable trimer in solution. The catalytic domain was overexpressed in Escherichia coli, and using a two-step procedure, it was possible to isolate monomeric and trimeric forms of AtCESA1CatD. The conformation of monomeric and trimeric AtCESA1CatD proteins were studied using small-angle neutron scattering and small-angle x-ray scattering. A series of AtCESA1CatD trimer computational models were compared with the small-angle x-ray scattering trimer profile to explore the possible arrangement of the monomers in the trimers. Several candidate trimers were identified with monomers oriented such that the newly synthesized cellulose chains project toward the cell membrane. In these models, the class-specific region is found at the periphery of the complex, and the plant-conserved region forms the base of the trimer. This study strongly supports the "hexamer of trimers" model for the rosette cellulose synthesis complex that synthesizes an 18-chain cellulose microfibril as its fundamental product.

Both the Strategic Defence and Security Review (SDSR) 2010 and Lord Levene’s ‘Defence Reform’ report of 2011 have again drawn attention to the variable performance of the Ministry of Defence (MoD) in acquisition matters and highlighted a number of underlying reasons along with a series of recommendations on how it could address them. Such a situation, where the MoD has to conduct a major transformation while managing a vast portfolio of activity, has been made all the more critical by the impact of the financial crisis and economic recession. To help reduce the UK’s budgetary deficit, defence is expected to deliver savings estimated at £4.3 billion by 2014-2015. This article looks at the current issues that are facing the UK MoD during this time of transition in respect of defence acquisition.

Peter D Antill, Jeremy CD Smith and David M Moore explain how the Ministry of Defence rushed through a set of urgent solutions to provide better protection for deployed personnel travelling in Armoured Fighting Vehicles (AFVs) and Protected Patrol Vehicles (PPVs) in Iraq and Afghanistan.

Cellobiohydrolase I (Cel7A) of the fungus Trichoderma reesei (now classified as an anamorph of Hypocrea jecorina) hydrolyzes crystalline cellulose to soluble sugars, making it of key interest for producing fermentable sugars from biomass for biofuel production. The activity of the enzyme is pH-dependent, with its highest activity occurring at pH 4-5. To probe the response of the solution structure of Cel7A to changes in pH, we measured small angle neutron scattering of it in a series of solutions having pH values of 7.0, 6.0, 5.3, and 4.2. As the pH decreases from 7.0 to 5.3, the enzyme structure remains well defined, possessing a spatial differentiation between the cellulose binding domain and the catalytic core that only changes subtly. At pH 4.2, the solution conformation of the enzyme changes to a structure that is intermediate between a properly folded enzyme and a denatured, unfolded state, yet the secondary structure of the enzyme is essentially unaltered. The results indicate that at the pH of optimal activity, the catalytic core of the enzyme adopts a structure in which the compact packing typical of a fully folded polypeptide chain is disrupted and suggest that the increased range of structures afforded by this disordered state plays an important role in the increased activity of Cel7A through conformational selection.

The folding and partitioning of WALP peptides into lipid bilayers is characterized using atomic detail molecular dynamics simulations on microsecond time scales. Elevated temperatures are used to increase sampling, and their suitability is validated via circular dichroism experiments. A new united atom parametrization of lipids is employed, adjusted for consistency with the OPLS allatom force field. In all simulations secondary structure forms rapidly, culminating in the formation of the native trans-membrane helix, which is demonstrated to have the lowest free energy. Partitioning simulations show that peptide insertion into the bilayer is preceded by interfacial folding. These results are in excellent agreement with partitioning theory. In contrast, previous simulations observed unfolded insertion pathways and incorrectly report stable extended configurations inside the membrane. This highlights the importance of accurately tuning and experimentally verifying force field parameters against microsecond time scale phenomena. © 2009 American Chemical Society.

GROMACS is one of the most widely used open-source and free software codes in chemistry, used primarily for dynamical simulations of biomolecules. It provides a rich set of calculation types, preparation and analysis tools. Several advanced techniques for free-energy calculations are supported. In version 5, it reaches new performance heights, through several new and enhanced parallelization algorithms. These work on every level; SIMD registers inside cores, multithreading, heterogeneous CPU–GPU acceleration, state-of-the-art 3D domain decomposition, and ensemble-level parallelization through built-in replica exchange and the separate Copernicus framework. The latest best-in-class compressed trajectory storage format is supported. Keywords: Molecular dynamics, GPU, SIMD, Free energy