Biomedical subjects

Fred P Davis

Publications and source records attributed to Fred P Davis.

7 recordsLinked to original sources

PubMed2006

Structural modeling of protein interactions by analogy: application to PSD-95.

We describe comparative patch analysis for modeling the structures of multidomain proteins and protein complexes, and apply it to the PSD-95 protein. Comparative patch analysis is a hybrid of comparative modeling based on a template complex and protein docking, with a greater applicability than comparative modeling and a higher accuracy than docking. It relies on structurally defined interactions of each of the complex components, or their homologs, with any other protein, irrespective of its fold. For each component, its known binding modes with other proteins of any fold are collected and expanded by the known binding modes of its homologs. These modes are then used to restrain conventional molecular docking, resulting in a set of binary domain complexes that are subsequently ranked by geometric complementarity and a statistical potential. The method is evaluated by predicting 20 binary complexes of known structure. It is able to correctly identify the binding mode in 70% of the benchmark complexes compared with 30% for protein docking. We applied comparative patch analysis to model the complex of the third PSD-95, DLG, and ZO-1 (PDZ) domain and the SH3-GK domains in the PSD-95 protein, whose structure is unknown. In the first predicted configuration of the domains, PDZ interacts with SH3, leaving both the GMP-binding site of guanylate kinase (GK) and the C-terminus binding cleft of PDZ accessible, while in the second configuration PDZ interacts with GK, burying both binding sites. We suggest that the two alternate configurations correspond to the different functional forms of PSD-95 and provide a possible structural description for the experimentally observed cooperative folding transitions in PSD-95 and its homologs. More generally, we expect that comparative patch analysis will provide useful spatial restraints for the structural characterization of an increasing number of binary and higher-order protein complexes.

Amino Acid Sequence↗

PubMed2006

Protein complex compositions predicted by structural similarity.

Proteins function through interactions with other molecules. Thus, the network of physical interactions among proteins is of great interest to both experimental and computational biologists. Here we present structure-based predictions of 3387 binary and 1234 higher order protein complexes in Saccharomyces cerevisiae involving 924 and 195 proteins, respectively. To generate candidate complexes, comparative models of individual proteins were built and combined together using complexes of known structure as templates. These candidate complexes were then assessed using a statistical potential, derived from binary domain interfaces in PIBASE (http://salilab.org/pibase). The statistical potential discriminated a benchmark set of 100 interface structures from a set of sequence-randomized negative examples with a false positive rate of 3% and a true positive rate of 97%. Moreover, the predicted complexes were also filtered using functional annotation and sub-cellular localization data. The ability of the method to select the correct binding mode among alternates is demonstrated for three camelid VHH domain-porcine alpha-amylase interactions. We also highlight the prediction of co-complexed domain superfamilies that are not present in template complexes. Through integration with MODBASE, the application of the method to proteomes that are less well characterized than that of S.cerevisiae will contribute to expansion of the structural and functional coverage of protein interaction space. The predicted complexes are deposited in MODBASE (http://salilab.org/modbase).

Algorithms↗

PubMed2006

MODBASE: a database of annotated comparative protein structure models and associated resources.

MODBASE (http://salilab.org/modbase) is a database of annotated comparative protein structure models for all available protein sequences that can be matched to at least one known protein structure. The models are calculated by MODPIPE, an automated modeling pipeline that relies on MODELLER for fold assignment, sequence-structure alignment, model building and model assessment (http:/salilab.org/modeller). MODBASE is updated regularly to reflect the growth in protein sequence and structure databases, and improvements in the software for calculating the models. MODBASE currently contains 3 094 524 reliable models for domains in 1 094 750 out of 1 817 889 unique protein sequences in the UniProt database (July 5, 2005); only models based on statistically significant alignments and models assessed to have the correct fold despite insignificant alignments are included. MODBASE also allows users to generate comparative models for proteins of interest with the automated modeling server MODWEB (http://salilab.org/modweb). Our other resources integrated with MODBASE include comprehensive databases of multiple protein structure alignments (DBAli, http://salilab.org/dbali), structurally defined ligand binding sites and structurally defined binary domain interfaces (PIBASE, http://salilab.org/pibase) as well as predictions of ligand binding sites, interactions between yeast proteins, and functional consequences of human nsSNPs (LS-SNP, http://salilab.org/LS-SNP).

Binding Sites↗

PubMed2005

Localization of protein-binding sites within families of proteins.

We address the question of whether or not the positions of protein-binding sites on homologous protein structures are conserved irrespective of the identities of their binding partners. First, for each domain family in the Structural Classification of Proteins (SCOP), protein-binding sites are extracted from our comprehensive database of structurally defined binary domain interactions (PIBASE). Second, the binding sites within each family are superposed using a structural alignment of its members. Finally, the degree of localization of binding sites within each family is quantified by comparing it with localization expected by chance. We found that 72% of the 1847 SCOP domain families in PIBASE have binding sites with localization values greater than expected by chance. Moreover, 554 (30%) of these families have localizations that are statistically significant (i.e., more than four standard deviations away from the mean expected by chance). In contrast, only 144 (8%) families have significantly low localization. The absence of a significant correlation of the binding site localization with the average sequence and structural conservations in a family suggests that localization can be helpful for describing the functional diversity of protein-protein interactions, complementing measures of sequence and structural conservation. Consideration of the binding site localization may also result in spatial restraints for the modeling of protein assembly structures.

Acyl-CoA Dehydrogenase↗

PubMed2005

PIBASE: a comprehensive database of structurally defined protein interfaces.

MOTIVATION: In recent years, the Protein Data Bank (PDB) has experienced rapid growth. To maximize the utility of the high resolution protein-protein interaction data stored in the PDB, we have developed PIBASE, a comprehensive relational database of structurally defined interfaces between pairs of protein domains. It is composed of binary interfaces extracted from structures in the PDB and the Probable Quaternary Structure server using domain assignments from the Structural Classification of Proteins and CATH fold classification systems. RESULTS: PIBASE currently contains 158,915 interacting domain pairs between 105,061 domains from 2125 SCOP families. A diverse set of geometric, physiochemical and topologic properties are calculated for each complex, its domains, interfaces and binding sites. A subset of the interface properties are used to remove interface redundancy within PDB entries, resulting in 20,912 distinct domain-domain interfaces. The complexes are grouped into 989 topological classes based on their patterns of domain-domain contacts. The binary interfaces and their corresponding binding sites are categorized into 18,755 and 30,975 topological classes, respectively, based on the topology of secondary structure elements. The utility of the database is illustrated by outlining several current applications. AVAILABILITY: The database is accessible via the world wide web at http://salilab.org/pibase SUPPLEMENTARY INFORMATION: http://salilab.org/pibase/suppinfo.html.

Algorithms↗

PubMed2004

MODBASE, a database of annotated comparative protein structure models, and associated resources.

MODBASE (http://salilab.org/modbase) is a relational database of annotated comparative protein structure models for all available protein sequences matched to at least one known protein structure. The models are calculated by MODPIPE, an automated modeling pipeline that relies on the MODELLER package for fold assignment, sequence-structure alignment, model building and model assessment (http:/salilab.org/modeller). MODBASE uses the MySQL relational database management system for flexible querying and CHIMERA for viewing the sequences and structures (http://www.cgl.ucsf.edu/chimera/). MODBASE is updated regularly to reflect the growth in protein sequence and structure databases, as well as improvements in the software for calculating the models. For ease of access, MODBASE is organized into different data sets. The largest data set contains 1,26,629 models for domains in 659,495 out of 1,182,126 unique protein sequences in the complete Swiss-Prot/TrEMBL database (August 25, 2003); only models based on alignments with significant similarity scores and models assessed to have the correct fold despite insignificant alignments are included. Another model data set supports target selection and structure-based annotation by the New York Structural Genomics Research Consortium; e.g. the 53 new structures produced by the consortium allowed us to characterize structurally 24,113 sequences. MODBASE also contains binding site predictions for small ligands and a set of predicted interactions between pairs of modeled sequences from the same genome. Our other resources associated with MODBASE include a comprehensive database of multiple protein structure alignments (DBALI, http://salilab.org/dbali) as well as web servers for automated comparative modeling with MODPIPE (MODWEB, http://salilab. org/modweb), modeling of loops in protein structures (MODLOOP, http://salilab.org/modloop) and predicting functional consequences of single nucleotide polymorphisms (SNPWEB, http://salilab. org/snpweb).

Amino Acid Sequence↗

PubMed2004

A structural perspective on protein-protein interactions.

Structures of macromolecular complexes are necessary for a mechanistic description of biochemical and cellular processes. They can be solved by experimental methods, such as X-ray crystallography, NMR spectroscopy and electron microscopy, as well as by computational protein structure prediction, docking and bioinformatics. Recent advances and applications of these methods emphasize the need for hybrid approaches that combine a variety of data to achieve better efficiency, accuracy, resolution and completeness.

Animals↗