Bioinformatics Advance Access originally published online on May 27, 2005
Bioinformatics 2005 21(15):3318-3319; doi:10.1093/bioinformatics/bti520
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COREX/BEST server: a web browser-based program that calculates regional stability variations within protein structures
Department of Human Biological Chemistry & Genetics, Sealy Center for Structural Biology, University of Texas Medical Branch at Galveston TX 77555, USA
*To whom correspondence should be addressed.
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Abstract |
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Summary: Utilizing the user-supplied coordinates of a protein structure, the COREX/BEST Server generates a structural thermodynamic ensemble. This conformational ensemble can then be used to calculate the regional variations in stability of a protein structure, and the stabilities are presented in units of energy (kcal/mol). The regional stabilities, which are calculated at the resolution of individual residues, can be mapped onto the protein structure for visual representation and downloaded from the site in the form of tab delimited text. The site provides an easy to follow summary of the theoretical and algorithmic approaches and provides links to references for more detailed descriptions.
Availability: The COREX/BEST Server may be accessed through a typical web browser by visiting http://best.utmb.edu/BEST/
Contact: vjhilser{at}utmb.edu
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INTRODUCTION |
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Although proteins are typically represented as static structures, it is well known that proteins are conformationally heterogeneous, owing to both small- and large-scale conformational fluctuations (Englander, 2000; Bai et al., 1995; Swint-Kruse and Robertson, 1996; Hvidt and Nielsen, 1966; Chamberlain et al., 1996; Radford et al., 1992). The structural and energetic features of these fluctuations are the subject of intense study, as are the effects of these fluctuations on such important biological processes as catalysis, allosterism and signal transduction (Lee et al., 2000; Volkman et al., 2001; Yang and Kay, 1996; Lu et al., 1998; Yang et al., 2003). Of particular importance for understanding these fluctuations are recent experimental results which indicate that the native ensemble of a protein is populated primarily by states that display a dual structural character, with some regions being compact and native-like, and other regions being highly solvated and displaying the thermodynamic signature of unfolded-like proteins (Pan et al., 2000; Ferreon et al., 2003; Babu et al., 2004; Whitten et al., 2005).
As a means of simulating these fluctuations, we have developed the COREX algorithm to model conformational excursions of the native structure as local folding/unfolding events that occur throughout the protein (Hilser and Freire, 1996; Hilser, 2001). Through use of a previously calibrated, extensively tested and parameterized energy function, a Boltzmann-weighted scheme has been successfully employed to calculate averaged properties of a protein's conformational ensemble for direct comparison to experimentally observed hydrogen–deuterium exchange (Hilser and Freire, 1996, 1997; Hilser et al., 1997; 1998), cold denaturation (Babu et al., 2004), allosteric binding effects (Pan et al., 2000) and pH-linked structural transitions (Whitten et al., 2005).
Here we describe the COREX/BEST (Biology through Ensemble-based Structural Thermodynamics) Server, a publicly available web interface that allows researchers to utilize these algorithmic tools to: (1) calculate a protein's conformational ensemble, (2) assess the relative stability differences within a protein's structure and (3) to determine the temperature-dependent stability of that conformational ensemble.
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PROGRAM FEATURE SUMMARY |
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TOPAbstractINTRODUCTIONPROGRAM FEATURE SUMMARYREQUIREMENTSPROGRAM DETAILSREFERENCES |
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- The COREX/BEST Server provides independent multi-user online access to an array of servers for the execution of the COREX/BEST algorithm, the performance of ancillary calculations and for saving calculated results in a series of user workspaces.
- The server provides the means for creation and management of individual user profiles and workspaces, which are managed through a web browser.
- The server allows uploading of user-specified protein structure files.
- Results of the COREX/BEST calculations are provided in various formats such as plain text, figures, structural graphics and/or compressed data, each of which may be downloaded to the user's personal computer.
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REQUIREMENTS |
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TOPAbstractINTRODUCTIONPROGRAM FEATURE SUMMARYREQUIREMENTSPROGRAM DETAILSREFERENCES |
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- A computer with a web browser and Internet capabilities is required to access the web-interface driven COREX/BEST Server.
- The web browser should be standards compliant (e.g., Mozilla Organization's Mozilla, Firefox or similar browsers are suggested).
- Sufficient data storage space is required for results of COREX/BEST calculations to be downloaded to user's computer.
- The COREX/BEST calculations require uploading a protein structure file written in plain text and in standard PDB file format to the COREX/BEST Server.
- Appropriate tools suggested for accessing any downloaded COREX/BEST results are: a text file reader, a spreadsheet program, an image viewer, and for cases involving the transfer of large data files, decompression tools. These tools are commonly included with current operating systems.
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PROGRAM DETAILS |
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Following successful registration at the COREX/BEST website, a typical user session consists of the following: (1) The user logs into the COREX/BEST Server through their web browser. (2) The user defines workspaces for each project. (3) The user uploads the protein structure file(s) to the appropriate workspace(s) on the COREX/BEST Server. Upon successful uploading, the server displays the protein structure in the user workspace. (4) At this point the user may submit a job(s) to the COREX/BEST server, which includes generation of a conformational ensemble, calculation of the regional stability within a protein and the temperature dependence of this stability. Final results are saved to the user workspace. As some jobs may require long execution times, depending on the current server load and the nature of the requested calculation, users receive email notification when jobs have been completed. (5) Finally, the user may download all or a subset of the calculated data contained within that user's workspace.
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Acknowledgments |
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This work was supported by grants from the NSF (MCB-9875689), NIH (GM13747) and the Welch Foundation (H-1461). J. V. is a Houston Area Molecular Biophysics Program (HAMBP) predoctoral fellow. Supported by NIH Molecular Biophysics Training Grant (T32 GM008280).
Conflict of Interest: none declared.
Received on January 18, 2005; revised on May 10, 2005; accepted on May 25, 2005
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REFERENCES |
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TOPAbstractINTRODUCTIONPROGRAM FEATURE SUMMARYREQUIREMENTSPROGRAM DETAILSREFERENCES |
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Babu, C.R., et al. (2004) Direct access to the cooperative substructure of proteins and the protein ensemble via cold denaturation. Nat. Struct. Biol., 11, 352–357.
Bai, Y., et al. (1995) Protein folding intermediates: native-state hydrogen exchange. Science, 269, 192–197
Chamberlain, A.K., et al. (1996) Detection of rare partially folded molecules in equilibrium with the native conformation of RNaseH. Nat. Struct. Biol., 3, 782–787[CrossRef][Web of Science][Medline].
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Ferreon, J.C., et al. (2003) Solution structure, dynamics, and thermodynamics of the native state ensemble of the sem-5 C-terminal SH3 domain. Biochemistry, 42, 5582–5591[CrossRef][Medline].
Hilser, V.J. (2001) Modeling the native state ensemble. Methods Mol. Biol., 168, 93–116[Medline].
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