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Efficient docking of peptides to proteins without prior knowledge of the binding site.

ABSTRACT: Reliability in docking of ligand molecules to proteins or other targets is an important challenge for molecular modeling. Applications of the docking technique include not only prediction of the binding mode of novel drugs, but also other problems like the study of protein-protein interactions. Here we present a study on the reliability of the results obtained with the popular AutoDock program. We have performed systematical studies to test the ability of AutoDock to reproduce eight different protein/ligand complexes for which the structure was known, without prior knowledge of the binding site. More specifically, we look at factors influencing the accuracy of the final structure, such as the number of torsional degrees of freedom in the ligand. We conclude that the Autodock program package is able to select the correct complexes based on the energy without prior knowledge of the binding site. We named this application blind docking, as the docking algorithm is not able to "see" the binding site but can still find it. The success of blind docking represents an important finding in the era of structural genomics.

SUBMITTER: Hetenyi C

PROVIDER: S-EPMC2373668 | biostudies-literature | 2002 Jul

REPOSITORIES: biostudies-literature

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Efficient docking of peptides to proteins without prior knowledge of the binding site.

Hetényi Csaba C van der Spoel David D

Protein science : a publication of the Protein Society 20020701 7

Reliability in docking of ligand molecules to proteins or other targets is an important challenge for molecular modeling. Applications of the docking technique include not only prediction of the binding mode of novel drugs, but also other problems like the study of protein-protein interactions. Here we present a study on the reliability of the results obtained with the popular AutoDock program. We have performed systematical studies to test the ability of AutoDock to reproduce eight different pr ...[more]

PMID: 12070326

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Project description:Site-specific chemical modification of proteins is important for many applications in biology and biotechnology. Recently, our laboratory and others have exploited the high specificity of the enzyme protein farnesyltransferase (PFTase) to site-specifically modify proteins through the use of alternative substrates that incorporate bioorthogonal functionality including azides and alkynes. In this study, we evaluate two aldehyde-containing molecules as substrates for PFTase and as reactants in both oxime and hydrazone formation. Using green fluorescent protein (GFP) as a model system, we demonstrate that the purified protein can be enzymatically modified with either analogue to yield aldehyde-functionalized proteins. Oxime or hydrazone formation was then employed to immobilize, fluorescently label, or PEGylate the resulting aldehyde-containing proteins. Immobilization via hydrazone formation was also shown to be reversible via transoximization with a fluorescent alkoxyamine. After characterizing this labeling strategy using pure protein, the specificity of the enzymatic process was used to selectively label GFP present in crude E. coli extract followed by capture of the aldehyde-modified protein using hydrazide-agarose. Subsequent incubation of the immobilized protein using a fluorescently labeled or PEGylated alkoxyamine resulted in the release of pure GFP containing the desired site-specific covalent modifications. This procedure was also employed to produce PEGylated glucose-dependent insulinotropic polypeptide (GIP), a protein with potential therapeutic activity for diabetes. Given the specificity of the PFTase-catalyzed reaction coupled with the ability to introduce a CAAX-box recognition sequence onto almost any protein, this method shows great potential as a general approach for selective immobilization and labeling of recombinant proteins present in crude cellular extract without prior purification. Beyond generating site-specifically modified proteins, this approach for polypeptide modification could be particularly useful for large-scale production of protein conjugates for therapeutic or industrial applications.

Dataset Information

Efficient docking of peptides to proteins without prior knowledge of the binding site.

Publications

Efficient docking of peptides to proteins without prior knowledge of the binding site.

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