When an experimentally determined protein structure is not available, homology or comparative modeling can frequently predict a useful model of a given sequence by relying on its similarity to proteins of known three-dimensional structure. The broad goal of the proposal is to increase the usefulness of comparative modeling for functional annotation of proteins. This goal will be achieved by automated methods that will minimize and detect errors in comparative models, and also be applicable to sequences only remotely related to known protein structures.
The specific aims are: 1. To increase the sensitivity of detecting known protein structures related to the modeled sequence, by identifying intermediate sequences matching both the known structure and the modeled sequence. 2. To minimize errors in protein sequence-structure alignments, by using an iterative process of alignment, model building, and model assessment, as well as structure and multiple sequence information. 3. To minimize model errors in sidechain packing, distortions and shifts in the core regions, and errors in the modeling of loops.
This aim will be achieved by relying on satisfaction of spatial restraints from template structures and energy terms from molecular mechanics, including an implicit solvation model. 4. To improve the assessment of the overall and local errors in a given comparative model, by relying on multivariate model assessment functions. 5. To automate and implement all the methods in the protein structure modeling program MODELLER. 6. To facilitate structure determination of the complete Saccharomyces cerevisiae ribosome, by providing comparative models for the fitting of proteins into the cryo-electron microscopy map of the ribosomal particle. Achieving these aims will augment other projects in the laboratory, including modeling of protein sequences on a genomic scale, a comprehensive database of models for all sequences detectably related to at least one known structure, and a web server for comparative protein structure modeling. More broadly, the specific aims are especially timely because of the advent of structural and functional genomics. The improvements will leverage the genomics effort by significantly increasing both the number of modeled proteins and the model accuracy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM054762-06
Application #
6399684
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Flicker, Paula F
Project Start
1996-06-01
Project End
2005-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
6
Fiscal Year
2001
Total Cost
$268,800
Indirect Cost
Name
Rockefeller University
Department
Physiology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Webb, Benjamin; Sali, Andrej (2016) Comparative Protein Structure Modeling Using MODELLER. Curr Protoc Bioinformatics 54:5.6.1-5.6.37
Webb, Benjamin; Lasker, Keren; Velázquez-Muriel, Javier et al. (2014) Modeling of proteins and their assemblies with the Integrative Modeling Platform. Methods Mol Biol 1091:277-95
Webb, Benjamin; Sali, Andrej (2014) Comparative Protein Structure Modeling Using MODELLER. Curr Protoc Bioinformatics 47:5.6.1-32
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Dong, Guang Qiang; Fan, Hao; Schneidman-Duhovny, Dina et al. (2013) Optimized atomic statistical potentials: assessment of protein interfaces and loops. Bioinformatics 29:3158-66
Fan, Hao; Hitchcock, Daniel S; Seidel 2nd, Ronald D et al. (2013) Assignment of pterin deaminase activity to an enzyme of unknown function guided by homology modeling and docking. J Am Chem Soc 135:795-803
Gradisar, Helena; Bozic, Sabina; Doles, Tibor et al. (2013) Design of a single-chain polypeptide tetrahedron assembled from coiled-coil segments. Nat Chem Biol 9:362-6
Lasker, Keren; Velázquez-Muriel, Javier A; Webb, Benjamin M et al. (2012) Macromolecular assembly structures by comparative modeling and electron microscopy. Methods Mol Biol 857:331-50

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