Computational protein design: validation and possible relevance as a tool for homology searching and fold recognition
| Autor: | Marcel Schmidt am Busch, Audrey Sedano, Thomas Simonson |
|---|---|
| Přispěvatelé: | Laboratoire de Biochimie de l'Ecole polytechnique (BIOC), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular MESH: Amino Acids MESH: Sequence Analysis Protein Entropy Biophysics/Protein Folding MESH: Protein Structure Secondary Computational Biology/Macromolecular Structure Analysis PDZ Domains Protein Structure Secondary Protein sequencing Protein structure Computational Biology/Protein Homology Detection Sequence Analysis Protein MESH: PDZ Domains MESH: Proteins Amino Acids Hidden Markov model Databases Protein MESH: Structural Homology Protein Genetics Multidisciplinary Protein Stability MESH: Entropy MESH: Reproducibility of Results Medicine MESH: Models Molecular MESH: Computational Biology Research Article MESH: Databases Protein Biophysics/Theory and Simulation MESH: Mutation Science Protein domain Protein design PDZ domain Sequence alignment Computational biology Biology MESH: Protein Stability Position-Specific Scoring Matrices [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Biophysics/Structural Genomics Computational Biology Proteins Reproducibility of Results MESH: Position-Specific Scoring Matrices Structural Homology Protein Mutation |
| Zdroj: | PLoS ONE, Vol 5, Iss 5, p e10410 (2010) PLoS ONE PLoS ONE, Public Library of Science, 2010, 5 (5), pp.e10410. ⟨10.1371/journal.pone.0010410⟩ |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0010410⟩ |
| Popis: | International audience; BACKGROUND: Protein fold recognition usually relies on a statistical model of each fold; each model is constructed from an ensemble of natural sequences belonging to that fold. A complementary strategy may be to employ sequence ensembles produced by computational protein design. Designed sequences can be more diverse than natural sequences, possibly avoiding some limitations of experimental databases. METHODOLOGY/PRINCIPAL FINDINGS: WE EXPLORE THIS STRATEGY FOR FOUR SCOP FAMILIES: Small Kunitz-type inhibitors (SKIs), Interleukin-8 chemokines, PDZ domains, and large Caspase catalytic subunits, represented by 43 structures. An automated procedure is used to redesign the 43 proteins. We use the experimental backbones as fixed templates in the folded state and a molecular mechanics model to compute the interaction energies between sidechain and backbone groups. Calculations are done with the Proteins@Home volunteer computing platform. A heuristic algorithm is used to scan the sequence and conformational space, yielding 200,000-300,000 sequences per backbone template. The results confirm and generalize our earlier study of SH2 and SH3 domains. The designed sequences ressemble moderately-distant, natural homologues of the initial templates; e.g., the SUPERFAMILY, profile Hidden-Markov Model library recognizes 85% of the low-energy sequences as native-like. Conversely, Position Specific Scoring Matrices derived from the sequences can be used to detect natural homologues within the SwissProt database: 60% of known PDZ domains are detected and around 90% of known SKIs and chemokines. Energy components and inter-residue correlations are analyzed and ways to improve the method are discussed. CONCLUSIONS/SIGNIFICANCE: For some families, designed sequences can be a useful complement to experimental ones for homologue searching. However, improved tools are needed to extract more information from the designed profiles before the method can be of general use. |
| Databáze: | OpenAIRE |
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