Development of an informatics infrastructure for data exchange of biomolecular simulations: Architecture, data models and ontology.

Biomolecular simulations aim to simulate structure, dynamics, interactions, and energetics of complex biomolecular systems. With the recent advances in hardware, it is now possible to use more complex and accurate models, but also reach time scales that are biologically significant. Molecular simulations have become a standard tool for toxicology and pharmacology research, but organizing and sharing data - both within the same organization and among different ones - remains a substantial challenge. In this paper we review our recent work leading to the development of a comprehensive informatics infrastructure to facilitate the organization and exchange of biomolecular simulations data. Our efforts include the design of data models and dictionary tools that allow the standardization of the metadata used to describe the biomedical simulations, the development of a thesaurus and ontology for computational reasoning when searching for biomolecular simulations in distributed environments, and the development of systems based on these models to manage and share the data at a large scale (iBIOMES), and within smaller groups of researchers at laboratory scale (iBIOMES Lite), that take advantage of the standardization of the meta data used to describe biomolecular simulations.

Nanoinformatics: developing new computing applications for nanomedicine.

Nanoinformatics has recently emerged to address the need of computing applications at the nano level. In this regard, the authors have participated in various initiatives to identify its concepts, foundations and challenges. While nanomaterials open up the possibility for developing new devices in many industrial and scientific areas, they also offer breakthrough perspectives for the prevention, diagnosis and treatment of diseases. In this paper, we analyze the different aspects of nanoinformatics and suggest five research topics to help catalyze new research and development in the area, particularly focused on nanomedicine. We also encompass the use of informatics to further the biological and clinical applications of basic research in nanoscience and nanotechnology, and the related concept of an extended "nanotype" to coalesce information related to nanoparticles. We suggest how nanoinformatics could accelerate developments in nanomedicine, similarly to what happened with the Human Genome and other -omics projects, on issues like exchanging modeling and simulation methods and tools, linking toxicity information to clinical and personal databases or developing new approaches for scientific ontologies, among many others.

Enabling GeneHunter as a grid service: a case study for implementing analytical services in biomedical grids.

BACKGROUND: A cursory analysis of the biomedical grid literature shows that most projects emphasize data sharing and the development of new applications for the grid environment. Much less is known about the best practices for the migration of existing analytical tools into the grid environment. OBJECTIVES: To make GeneHunter available as a grid service and to evaluate the effort and best practices needed to enable a legacy application as a grid service when addressing semantic integration and using the caBIG tools. METHODS: We used the tools available in the caBIG environment because these tools are quite general and they may be used to deploy services in similar biomedical grids that are OGSA-compliant. RESULTS: We achieved semantic integration of GeneHunter within the caBIG by creating a new UML model, LinkageX, for the LINKAGE data format. The LinkageX UML model has been published in the caDSR and it is publically available for usage with GeneHunter or any other program using this data format. CONCLUSIONS: While achieving semantic interoperability is still a time-consuming task, the tools available in caBIG can greatly enhance productivity and decrease errors.

A third blind test of crystal structure prediction.

Following the interest generated by two previous blind tests of crystal structure prediction (CSP1999 and CSP2001), a third such collaborative project (CSP2004) was hosted by the Cambridge Crystallographic Data Centre. A range of methodologies used in searching for and ranking the likelihood of predicted crystal structures is represented amongst the 18 participating research groups, although most are based on the global minimization of the lattice energy. Initially the participants were given molecular diagrams of three molecules and asked to submit three predictions for the most likely crystal structure of each. Unlike earlier blind tests, no restriction was placed on the possible space group of the target crystal structures. Furthermore, Z' = 2 structures were allowed. Part-way through the test, a partial structure report was discovered for one of the molecules, which could no longer be considered a blind test. Hence, a second molecule from the same category (small, rigid with common atom types) was offered to the participants as a replacement. Success rates within the three submitted predictions were lower than in the previous tests - there was only one successful prediction for any of the three ;blind' molecules. For the ;simplest' rigid molecule, this lack of success is partly due to the observed structure crystallizing with two molecules in the asymmetric unit. As in the 2001 blind test, there was no success in predicting the structure of the flexible molecule. The results highlight the necessity for better energy models, capable of simultaneously describing conformational and packing energies with high accuracy. There is also a need for improvements in search procedures for crystals with more than one independent molecule, as well as for molecules with conformational flexibility. These are necessary requirements for the prediction of possible thermodynamically favoured polymorphs. Which of these are actually realised is also influenced by as yet insufficiently understood processes of nucleation and crystal growth.

Modeling solid-state effects on NMR chemical shifts using electrostatic models.

This paper presents a comparison of the embedded ion method (EIM) and the surface charge representation of the electrostatic embedding potential (SCREEP) method, two methods which can be used to calculate solid-state effects on NMR chemical shifts. The results in a selected group of compounds with known single-crystal solid-state NMR data and neutron diffraction structures, confirm that these effects are important in both (13)C and (15)N chemical shifts. The solid-state effects calculated by both methods are similar and of equal statistical quality when compared with the experimental data.

Modeling NMR chemical shifts: a comparison of charge models for solid state effects on 15N chemical shift tensors.

This paper presents results from applying different point charge models to take into account intermolecular interactions to model the solid state effects on the 15N NMR chemical shifts tensors. The DFT approach with the BLYP gradient corrected exchange correlation functional has been used because it can include electron correlation effects at a reasonable cost and is able to reproduce 15N NMR chemical shifts with reasonable accuracy. The results obtained with the point charge models are compared with the experimental data and with results obtained using the cluster model, which includes explicitly neighboring molecular fragments. The results show that the point charge models can take into account solid state effects at a cost much lower than the cluster methods.

Nitrogen-15 chemical shifts in AT (adenine-thymine) and CG (cytosine-guanine) nucleic acid base pairs.

This paper presents ab initio (DFT) calculations of the 15N chemical shifts in AT (Adenine-Thymine) and CG (Cytosine-Guanine) nucleic acid base pairs. Calculations were done on 14 AT and 18 CG base pairs using experimental (X-ray) geometries obtained from several DNA decamers. The calculated chemical shifts are compared with the experimental values in the pure bases and subjected to statistical analysis to explore their sensitivity to the local geometry and pair helix parameters. The results indicate that the 15N chemical shifts, isotropic and principal components are quite sensitive to small changes in the geometry of the pairs, but they do not correlate well with the helix pair parameters. From the statistical analysis, several linear correlations between structural parameters and chemical shifts emerge. These relationships may serve as a foundation to extract information on molecular structure from 15N chemical shift measurements.

Quantum mechanical calculations and experimental measurement of N-terminal charge effects on 1HN and 1HC alpha chemical shifts in peptides.

Nuclear magnetic resonance spectroscopists are increasingly utilizing chemical shifts to characterize the secondary structure of proteins. The present study addresses the effects that the positively charged amino group at the N-terminus of a peptide has on 1HN and 1HC alpha chemical shifts along the chain. This information is necessary for interpreting chemical shift data for proteins and/or for peptides that are used as models for protein structure. The chemical shifts for the 1H resonances of four peptides that differ only in the location of their N-terminii are assigned using two-dimensional nmr spectroscopy. The peptides have sequences derived from the beta subunit of the glycoprotein hormone human chorionic gonadotropin (hCG-beta). Comparison of the 1HN and the 1HC alpha chemical shifts for residues common to all four peptides reveals downfield shifts for 1HN and the 1HC alpha resonances within three residues of the N-terminus compared with chemical shifts in the interior of the peptide. The magnitude of the downfield shift is larger for resonances nearer the N-terminus. Quantum mechanical calculations of the 1HN and 1HC alpha chemical shifts in peptides constructed with six alanine units also predict a significant terminus effect. The calculations agree both qualitatively and quantitatively with the experimental data. The inductive nature of the end effect is confirmed in the calculations by Mulliken population analysis. End effects should be taken into account in determining protein secondary structures from chemical shifts.

Relationship of 13C NMR chemical shift tensors to diffraction structures.

13C chemical shift tensor measurements on single crystals provide a powerful method to study changes in the electron environment of nuclei with changes in molecular structure. Thus, diffraction structures are critical to an understanding of chemical shift tensors. This work explores the general reliability of using structural data to predict components of the symmetrical chemical shift tensor. Imprecision in the hydrogen positions introduces considerable scatter in the simulated 13C shift tensors, and optimized C-H bond distances in methyl-beta-D-glucopyranoside used with the X-ray positions of the heavier C and O atoms greatly improve the simulated chemical shifts. Acenaphthene, with two crystallographically different molecules per unit cell, offers an excellent example for comparing and contrasting structural differences in the two molecules. A recently improved X-ray structure of naphthalene obtained at low temperature provides chemical shift simulations which are comparable to those from neutron diffraction methods and appear to reflect breaks in the D2h symmetry measured in the NMR chemical shift tensors. These data illustrate the close relationship between NMR and diffraction structures.

Determination of molecular symmetry in crystalline naphthalene using solid-state NMR.

Diffraction techniques have shown that the crystal structure of naphthalene has a unit cell with Ci symmetry. These studies were unable, however, to resolve any departure of the molecular structure from the D2h symmetry observed in the gaseous state. We found recently that the solid-state 13C-nuclear magnetic resonance (NMR) chemical shifts for naphthalene exhibit the Ci symmetry of the unit cell. If these chemical-shift data reflect structural distortions of the molecule, rather than simply intermolecular effects on the shifts owing to the Ci symmetry of the environment of each molecule, one could assert that the NMR data are able to reveal structural information beyond the limits of the diffraction methods. Here we show that this is the case by performing ab initio quantum-mechanical calculations of the 13C chemical shifts for naphthalene, and their derivatives, with respect to structural parameters. We find that intermolecular shift terms (which of necessity exhibit Ci symmetry) can account for only about 30% of the maximum deviations from D2h symmetry; the remainder must therefore result from structural distorations of the molecules below D2h symmetry. This sensitivity of NMR chemical shifts to very small changes in molecular structure opens up the possibility of using solid-state NMR along with quantum-chemical methods to refine structural parameters obtained from diffraction methods.