Functional region prediction with a set of appropriate homologous sequences-an index for sequence selection by integrating structure and sequence information with spatial statistics.
ABSTRACT BACKGROUND: The detection of conserved residue clusters on a protein structure is one of the effective strategies for the prediction of functional protein regions. Various methods, such as Evolutionary Trace, have been developed based on this strategy. In such approaches, the conserved residues are identified through comparisons of homologous amino acid sequences. Therefore, the selection of homologous sequences is a critical step. It is empirically known that a certain degree of sequence divergence in the set of homologous sequences is required for the identification of conserved residues. However, the development of a method to select homologous sequences appropriate for the identification of conserved residues has not been sufficiently addressed. An objective and general method to select appropriate homologous sequences is desired for the efficient prediction of functional regions. RESULTS: We have developed a novel index to select the sequences appropriate for the identification of conserved residues, and implemented the index within our method to predict the functional regions of a protein. The implementation of the index improved the performance of the functional region prediction. The index represents the degree of conserved residue clustering on the tertiary structure of the protein. For this purpose, the structure and sequence information were integrated within the index by the application of spatial statistics. Spatial statistics is a field of statistics in which not only the attributes but also the geometrical coordinates of the data are considered simultaneously. Higher degrees of clustering generate larger index scores. We adopted the set of homologous sequences with the highest indexscore, under the assumption that the best prediction accuracy is obtained when the degree of clustering is the maximum. The set of sequences selected by the index led to higher functional region prediction performance than the sets of sequences selected by other sequence-based methods. CONCLUSIONS: Appropriate homologous sequences are selected automatically and objectively by the index. Such sequence selection improved the performance of functional region prediction. As far as we know, this is the first approach in which spatial statistics have been applied t o protein analyses. Such integration of structure and sequence information would be useful for other bioinformatics problems.
Article: Adolescent precursors of intensity of marijuana and other illicit drug use among adult initiators.[show abstract] [hide abstract]
ABSTRACT: This study examined (a) adolescent psychosocial risk factors for frequency (intensity) of marijuana use and for other illicit drug use among those who started using these drugs in early adulthood (adult initiators) and (b) the protective role of parent-adolescent relations in reducing or preventing drug use when adolescents enter early adulthood. The study's participants were male and female youth from a longitudinal prospective study. The participants' mean ages were 17 and 22 years at late adolescence and early adulthood, respectively. Independent measures assessed personality, parental, peer, and self-drug-use factors during late adolescence; dependent measures assessed frequency of marijuana use and other illicit drug use during early adulthood for initiators of the respective drug categories. The authors found that intensity of marijuana use was directly associated with the personality, parental, and self-drug-use domains and indirectly associated with the peer domain. Intensity of other illicit drug use was directly associated with personality and self-drug use. Analyses also revealed that some parent-adolescent relations factors buffered the effects of risk factors for both marijuana and other illicit drug-use intensity, whereas others enhanced the effects of protective factors against other illicit drug-use intensity. The results indicate that there are both commonalities and differences in precursors of marijuana and other illicit drug-use intensity among initiators of these drugs during early adulthood.The Journal of Genetic Psychology 01/2002; 162(4):430-50. · 0.49 Impact Factor
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ABSTRACT: X-ray or NMR structures of proteins are often derived without their ligands, and even when the structure of a full complex is available, the area of contact that is functionally and energetically significant may be a specialized subset of the geometric interface deduced from the spatial proximity between ligands. Thus, even after a structure is solved, it remains a major theoretical and experimental goal to localize protein functional interfaces and understand the role of their constituent residues. The evolutionary trace method is a systematic, transparent and novel predictive technique that identifies active sites and functional interfaces in proteins with known structure. It is based on the extraction of functionally important residues from sequence conservation patterns in homologous proteins, and on their mapping onto the protein surface to generate clusters identifying functional interfaces. The SH2 and SH3 modular signaling domains and the DNA binding domain of the nuclear hormone receptors provide tests for the accuracy and validity of our method. In each case, the evolutionary trace delineates the functional epitope and identifies residues critical to binding specificity. Based on mutational evolutionary analysis and on the structural homology of protein families, this simple and versatile approach should help focus site-directed mutagenesis studies of structure-function relationships in macromolecules, as well as studies of specificity in molecular recognition. More generally, it provides an evolutionary perspective for judging the functional or structural role of each residue in protein structure.Journal of Molecular Biology 04/1996; 257(2):342-58. · 4.00 Impact Factor