A Robust Water Potential Parameterisation

Abstract

We compare molecular dynamics simulation results for the properties of liquid water predicted by four novel water potential models. These models are designed as a combination of parameters taken from the dedicated but brittle TIP3P water potential, and the more flexible but less accurate parameterisations such as the Dreiding and Universal force fields. We find that a hybrid of Dreiding and TIP3P delivers the best results, yielding a density, diffusion coefficient and radial distribution function in good agreement with experiment, performing in some respects even better than the dedicated reference TIP3P model. Another Dreiding based force field predicts semi-quantitative results for the water structure and dynamics while the Universal force field based models are incapable of simulating a condensed phase of water at all, continuing to expand indefinitely. These observations are useful for selecting and designing robust water force field parameterisations that can be used for general simulation purposes.     

Quantized Water Access to the HIV-1 Protease Active Site as a Proposed Mechanism for Cooperative Mutations in Drug Affinity

The development of resistance to different drugs remains a major problem for a wide range of infections. In particular, combinations of specific mutations, which individually demonstrate no effect, exhibit significant cooperativity. Here we show that changes to the energy of ligand binding in different resistant HIV-1 proteases are correlated with the creation of water binding sites in the active site. This correlation is conserved across two drugs (ritonavir and lopinavir). We propose that individual mutations induce changes in flap packing that are insufficient to allow water binding but in combination allow access, leading to the observed cooperative resistance.     

A microsatellite-based consensus linkage map for species of Eucalyptus and a novel set of 230 microsatellite markers for the genus

Background  

Eucalypts are the most widely planted hardwood trees in the world occupying globally more than 18 million hectares as an important source of carbon neutral renewable energy and raw material for pulp, paper and solid wood. Quantitative Trait Loci (QTLs) in Eucalyptus have been localized on pedigree-specific RAPD or AFLP maps seriously limiting the value of such QTL mapping efforts for molecular breeding. The availability of a genus-wide genetic map with transferable microsatellite markers has become a must for the effective advancement of genomic undertakings. This report describes the development of a novel set of 230 EMBRA microsatellites, the construction of the first comprehensive microsatellite-based consensus linkage map for Eucalyptus and the consolidation of existing linkage information for other microsatellites and candidate genes mapped in other species of the genus.     

Is the behaviour of the leg during oscillation linear?

The linear behaviour of the human leg was studied using a free oscillation method. The lower leg is represented by a simple mass, spring and dashpot model. Forty-five subjects underwent free vibration tests on their right legs. The force amplitude and the time period, for successive oscillations enabled calculation of the stiffness to mass ratio values. It was found that the time period of the second oscillation cycle was significantly lower than that of the first, implying a corresponding increase in stiffness. The experimental data consistently exhibits these non-linear characteristics, indicating that the use of non-linear models could be of benefit for future free oscillation studies.     

NEKTAR,SPICE and Vortonics: using federated grids for large scale scientific applications

In response to a joint call from US’s NSF and UK’s EPSRC for applications that aim to utilize the combined computational resources of the US and UK, three computational science groups from UCL, Tufts and Brown Universities teamed up with a middleware team from NIU/Argonne to meet the challenge. Although the groups had three distinct codes and aims, the projects had the underlying common feature that they were comprised of large-scale distributed applications which required high-end networking and advanced middleware in order to be effectively deployed. For example, cross-site runs were found to be a very effective strategy to overcome the limitations of a single resource. The seamless federation of a grid-of-grids remains difficult. Even if interoperability at the middleware and software stack levels were to exist, it would not guarantee that the federated grids can be utilized for large scale distributed applications. There are important additional requirements for example, compatible and consistent usage policy, automated advanced reservations and most important of all co-scheduling. This paper outlines the scientific motivation and describes why distributed resources are critical for all three projects. It documents the challenges encountered in using a grid-of-grids and some of the solutions devised in response.     

Symmetry-breaking in Chiral Polymerisation

We propose a model for chiral polymerisation and investigate its symmetric and asymmetric solutions. The model has a source species which decays into left- and right-handed types of monomer, each of which can polymerise to form homochiral chains; these chains are susceptible to ‘poisoning’ by the opposite-handed monomer. Homochiral polymers are assumed to influence the proportion of each type of monomer formed from the precursor. We show that for certain parameter values a positive feedback mechanism makes the symmetric steady-state solution unstable. The kinetics of polymer formation are then analysed in the case where the system starts from zero concentrations of monomers and chains. We show that following a long induction time, extremely large concentrations of polymers are formed for a short time, during this time an asymmetry introduced into the system by a random external perturbation may be massively amplified. The system then approaches one of the steady-state solutions described above.     

A computational protocol for the integration of the monotopic protein prostaglandin H2 synthase into a phospholipid bilayer

Prostaglandin H2 synthase (PGHS) synthesizes PGH2, a prostaglandin precursor, from arachidonic acid and was the first monotopic enzyme to have its structure experimentally determined. Both isozymes of PGHS are inhibited by nonsteroidal antiinflammatory drugs, an important class of drugs that are the primary means of relieving pain and inflammation. Selectively inhibiting the second isozyme, PGHS-2, minimizes the gastrointestinal side-effects. This had been achieved by the new PGHS-2 selective NSAIDs (i.e., COX-2 inhibitors) but it has been recently suggested that they suffer from additional side-effects. The design of these drugs only made use of static structures from x-ray crystallographic experiments. Investigating the dynamics of both PGHS-1 and PGHS-2 using classical molecular dynamics is expected to generate new insight into the differences in behavior between the isozymes, and therefore may allow improved PGHS-2 selective inhibitors to be designed. We describe a molecular dynamics protocol that integrates PGHS monomers into phospholipid bilayers, thereby producing in silico atomistic models of the PGHS system. Our protocol exploits the vacuum created beneath the protein when several lipids are removed from the top leaflet of the bilayer. The protein integrates into the bilayer during the first 5 ns in a repeatable process. The integrated PGHS monomer is stable and forms multiple hydrogen bonds between the phosphate groups of the lipids and conserved basic residues (Arg, Lys) on the protein. These interactions stabilize the system and are similar to interactions observed for transmembrane proteins.     

Molecular Modelling of The Mechanism of Action of Organic Clay-Swelling Inhibitors

Abstract

It is well known that the sodium smectite class of clays swells macroscopically in contact with water, whereas under normal conditions the potassium form does not. In recent work using molecular simulation methods, we have provided a quantitative explanation both for the swelling behaviour of sodium smectite clays and the lack of swelling of potassium smectites [1]. In the present paper, we apply similar modelling methods to study the mechanism of inhibition of clay-swelling by a range of organic molecules.

Experimentally, it is known that polyalkylene glycols (polyethers) of intermediate to high relative molecular mass are effective inhibitors of smectite clay swelling. We use a range of atomistic simulation techniques, including Monte Carlo and molecular dynamics, to investigate the interactions between a selection of these compounds, water, and a model smectite clay mineral. These interactions occur by means of organised intercalation of water and organic molecules within the galleries between individual clay layers.

The atomic interaction potentials deployed in this work are not as highly optimised as those used in our clay-cation-water work [1]. Nevertheless, our simulations yield trends and results that are in qualitative and sometimes semi-quantitative agreement with experimental findings on similiar (but not identical) systems. The internal energy of adsorption of simple polyethers per unit mass on the model clay is not significantly different from that for water adsorption; our Monte Carlo studies indicate that entropy is the driving force for the sorption of the simpler organic molecules inside the clay layers: a single long chain polyethylene glycol can displace a large number of water molecules, each of whose translational entropy is greatly enhanced when outside the clay. Hydrophobically modified polyalkylene glycols also enjoy significant van der Waals interactions within the layers which they form within the clay galleries.

In conjunction with experimental studies, our work furnishes valuable insights into the relative effectiveness of the compounds considered and reveals the generic features that high performance clay-swelling inhibitors should possess. For optimal inhibitory activity, these compounds should be reasonably long chain linear organic molecules with localised hydrophobic and hydrophilic regions along the chain. On intercalation of these molecules within the clay layers, the hydrophobic regions provide an effective seal against ingress of water, while the hydrophilic ones enhance the binding of the sodium cations to the clay surface, preventing their hydration and the ensuing clay swelling.