The WeNMR (http://www.wenmr.eu) project is an EU-funded international effort to streamline and automate structure determination from Nuclear Magnetic Resonance (NMR) data. Conventionally calculation of structure requires the use of various softwares, considerable user expertise and ample computational resources. To facilitate the use of NMR spectroscopy in life sciences the eNMR/WeNMR consortium has set out to provide protocolized services through easy-to-use web interfaces, while still retaining sufficient flexibility to handle more specific requests. Thus far, a

One of the central challenges in structural molecular biology today is the protein folding problem, i.e. the acquisition of the 3D structure of a protein from its linear sequence of amino-acids. Different computational approaches to study protein folding and protein unfolding have recently become common tools available to the researcher. However, due to the lack of appropriate infrastructures, it is very difficult to directly compare simulations performed by different groups, with different methods, in different experimental conditions or for different proteins. Thus, we set out to create a public data repository with the goal of addressing the problem of comparison, analysis and sharing of information and data on protein folding and protein unfolding simulations. The P-found system for protein folding and protein unfolding simulations is presented. At the moment, the data repository allows uploading of molecular dynamics (MD) protein folding and unfolding simulations, calculates and stores several time series with the variation over time of pre-defined molecular properties, and allows searching and downloading of these data. In the near future, simulations performed by other than MD methods may be uploaded, and data mining techniques for analysis and comparison of multiple simulations will be implemented. The home page for the P-found system is accessible at http://www.p-found.org.

A docking-and-alignment protocol was devised in order to build amyloid protofilaments of Transthyretin (TTR), starting from partially disrupted TTR monomeric subunits and based on experimentally available information. The docking approach is driven by a combination of shape complementarity and energetic criteria, and uses constraints derived from experimental data obtained for the fibrillar state. The dimeric structures obtained were then subjected to an alignment scheme followed by clustering analysis, producing a collection of protofilaments with distinct geometric properties. The selected protofilament model presented here does agree with known experimental data and general amyloid properties; it is formed by two extended continuous b-sheets with the b-strands perpendicular to the main axis of the protofilament and a helical twist with a period of ,48 b-strands. This TTR protofilament model may be an important step in the understanding of the molecular mechanisms of TTR aggregation, as well as, a valuable instrument in drug design strategies against amyloid diseases.Keywords: Transthyretin; amyloid; protofilament; protein docking; supramolecular assembly Transthyretin (TTR) is one of several proteins known to be involved in human amyloid diseases. TTR is a homotetrameric protein mostly found in the plasma and the cerebral spinal fluid, and has been identified as the causative agent of such diseases as Familial Amyloidotic Polyneuropathy, Familial Amyloidotic Cardiomyopathy, and Senile Systemic Amyloidosis. It is believed that, in the process of amyloid formation, TTR dissociates to nonnative monomeric units, which may act as the building blocks of the amyloid fibrils (Lai et al. 1996;Quintas et al. 1999Quintas et al. , 2001; for review, see Brito et al. 2003). The structural characterization of these fibrils and the identification of the entities involved in fibril assembly are crucial for understanding of the mechanisms of pathogenesis in amyloid diseases, and for the development of appropriate therapeutic strategies. Experimental techniques have not yet been able to produce a high-resolution structure of an amyloid fibril of TTR. The work presented here proposes a high-resolution working model of the elementary units that constitute the fibrils, the protofilaments.Each TTR subunit has a b-sandwich fold composed of two four-stranded b-sheets labeled DAGH and CBEF, as shown in Figure 1. In the native protein, the b-sheets from two monomers associate edge-to-edge through b-strands H/H¢ and F/F¢ to produce a dimer composed of two extended b-sheets formed by strands DAGHH¢G¢A¢D¢ and CBEFF¢E¢B¢C¢. Association of two of these dimers mainly through hydrophobic interactions mediated by the AB and GH loops forms the functional homotetramer. Abbreviations: EPR, electron paramagnetic resonance; NearNI, nearnative interface; NonNI, non-native interface; TTR, Transthyretin.Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi

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