A topology-based investigation of protein interaction sites using Hydrophobic Cluster Analysis.

Hydrophobic clusters, as defined by Hydrophobic Cluster Analysis (HCA), are conditioned binary patterns, made of hydrophobic and non-hydrophobic positions, whose limits fit well those of regular secondary structures. They were proved to be useful for predicting secondary structures in proteins from the only information of a single amino acid sequence and have permitted to assess, in a comprehensive way, the leading role of binary patterns in secondary structure preference towards a particular state. Here, we considered the available experimental 3D structures of protein globular domains to enlarge our previously reported hydrophobic cluster database (HCDB), almost doubling the number of hydrophobic cluster species (each species being defined by a unique binary pattern) that represent the most frequent structural bricks encountered within protein globular domains. We then used this updated HCDB to show that the hydrophobic amino acids of discordant clusters, i.e. those less abundant clusters for which the observed secondary structure is in disagreement with the binary pattern preference of the species to which they belong, are more exposed to solvent and are more involved in protein interfaces than the hydrophobic amino acids of concordant clusters. As amino acid composition differs between concordant/discordant clusters, considering binary patterns may be used to gain novel insights into key features of protein globular domain cores and surfaces. It can also provide useful information on possible conformational plasticity, including disorder to order transitions.

The respective roles of polar/nonpolar binary patterns and amino acid composition in protein regular secondary structures explored exhaustively using hydrophobic cluster analysis.

Several studies have highlighted the leading role of the sequence periodicity of polar and nonpolar amino acids (binary patterns) in the formation of regular secondary structures (RSS). However, these were based on the analysis of only a few simple cases, with no direct mean to correlate binary patterns with the limits of RSS. Here, HCA-derived hydrophobic clusters (HC) which are conditioned binary patterns whose positions fit well those of RSS, were considered. All the HC types, defined by unique binary patterns, which were commonly observed in three-dimensional (3D) structures of globular domains, were analyzed. The 180 HC types with preferences for either α-helices or ß-strands distinctly contain basic binary units typical of these RSS. Therefore a general trend supporting the "binary pattern preference" assumption was observed. HC for which observed RSS are in disagreement with their expected behavior (discordant HC) were also examined. They were separated in HC types with moderate preferences for RSS, having "weak" binary patterns and versatile RSS and HC types with high preferences for RSS, having "strong" binary patterns and then displaying nonpolar amino acids at the protein surface. It was shown that in both cases, discordant HC could be distinguished from concordant ones by well-differentiated amino acid compositions. The obtained results could, thus, help to complement the currently available methods for the accurate prediction of secondary structures in proteins from the only information of a single amino acid sequence. This can be especially useful for characterizing orphan sequences and for assisting protein engineering and design.

Determination of French influenza outbreaks periods between 1985 and 2011 through a web-based Delphi method.

BACKGROUND: Assessing the accuracy of influenza epidemic periods determined by statistical models is important to improve the performance of algorithms used in real-time syndromic surveillance systems. This is a difficult problem to address in the absence of a reliable gold standard. The objective of this study is to establish an expert-based determination of the start and the end of influenza epidemics in France. METHODS: A three-round international web-based Delphi survey was proposed to 288 eligible influenza experts. Fifty-seven (20%) experts completed the three-rounds of the study. The experts were invited to indicate the starting and the ending week of influenza epidemics, on 32 time-series graphs of influenza seasons drawn using data from the French Sentinelles Network (Influenza-like illness incidence rates) and virological data from the WHO-FluNet. Twenty-six of 32 time-series graphs proposed corresponded to each of the French influenza seasons observed between 1985 and 2011. Six influenza seasons were proposed twice at each round to measure variation among expert responses. RESULTS: We obtained consensual results for 88% (23/26) of the epidemic periods. In two or three rounds (depending on the season) answers gathered around modes, and the internal control demonstrated a good reproducibility of the answers. Virological data did not appear to have a significant impact on the answers or the level of consensus, except for a season with a major mismatch between virological and incidence data timings. CONCLUSIONS: Thanks to this international web-based Delphi survey, we obtained reproducible, stable and consensual results for the majority of the French influenza epidemic curves analysed. The detailed curves together with the estimates from the Delphi study could be a helpful tool for assessing the performance of statistical outbreak detection methods, in order to optimize them.

Ligand scaffold hopping combining 3D maximal substructure search and molecular similarity.

BACKGROUND: Virtual screening methods are now well established as effective to identify hit and lead candidates and are fully integrated in most drug discovery programs. Ligand-based approaches make use of physico-chemical, structural and energetics properties of known active compounds to search large chemical libraries for related and novel chemotypes. While 2D-similarity search tools are known to be fast and efficient, the use of 3D-similarity search methods can be very valuable to many research projects as integration of "3D knowledge" can facilitate the identification of not only related molecules but also of chemicals possessing distant scaffolds as compared to the query and therefore be more inclined to scaffolds hopping. To date, very few methods performing this task are easily available to the scientific community. RESULTS: We introduce a new approach (LigCSRre) to the 3D ligand similarity search of drug candidates. It combines a 3D maximum common substructure search algorithm independent on atom order with a tunable description of atomic compatibilities to prune the search and increase its physico-chemical relevance. We show, on 47 experimentally validated active compounds across five protein targets having different specificities, that for single compound search, the approach is able to recover on average 52% of the co-actives in the top 1% of the ranked list which is better than gold standards of the field. Moreover, the combination of several runs on a single protein target using different query active compounds shows a remarkable improvement in enrichment. Such Results demonstrate LigCSRre as a valuable tool for ligand-based screening. CONCLUSION: LigCSRre constitutes a new efficient and generic approach to the 3D similarity screening of small compounds, whose flexible design opens the door to many enhancements. The program is freely available to the academics for non-profit research at: http://bioserv.rpbs.univ-paris-diderot.fr/LigCSRre.html.