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Computational protein design: validation and possible relevance as a tool for homology searching and fold recognition.

Schmidt Am Busch M, Sedano A, Simonson T - PLoS ONE (2010)

Bottom Line: The results confirm and generalize our earlier study of SH2 and SH3 domains.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Biochimie (CNRS UMR7654), Department of Biology, Ecole Polytechnique, Palaiseau, France.

ABSTRACT

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.

Show MeSH
Designed sequences detected as PDZ domains or chemokines by SUPERFAMILY, CDD, and PSI-BLAST.Each column corresponds to one of the backbone templates. For each template, results are shown for the 8,000 lowest-energy sequences.
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pone-0010410-g003: Designed sequences detected as PDZ domains or chemokines by SUPERFAMILY, CDD, and PSI-BLAST.Each column corresponds to one of the backbone templates. For each template, results are shown for the 8,000 lowest-energy sequences.

Mentions: The SUPERFAMILY HMM library yielded the correct family assignment for the vast majority of designed sequences (Table 2): almost 100% for SKIs and chemokines, and over 90% for caspases and PDZ domains. The 8,000 lowest-energy designed sequences outperformed the random sequences, except for the R55 ones (55% identity to the caspase templates; see Table 2 and Figure 3). The designed caspases outperform the R45 and R35 random sequences.


Computational protein design: validation and possible relevance as a tool for homology searching and fold recognition.

Schmidt Am Busch M, Sedano A, Simonson T - PLoS ONE (2010)

Designed sequences detected as PDZ domains or chemokines by SUPERFAMILY, CDD, and PSI-BLAST.Each column corresponds to one of the backbone templates. For each template, results are shown for the 8,000 lowest-energy sequences.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2864755&req=5

pone-0010410-g003: Designed sequences detected as PDZ domains or chemokines by SUPERFAMILY, CDD, and PSI-BLAST.Each column corresponds to one of the backbone templates. For each template, results are shown for the 8,000 lowest-energy sequences.
Mentions: The SUPERFAMILY HMM library yielded the correct family assignment for the vast majority of designed sequences (Table 2): almost 100% for SKIs and chemokines, and over 90% for caspases and PDZ domains. The 8,000 lowest-energy designed sequences outperformed the random sequences, except for the R55 ones (55% identity to the caspase templates; see Table 2 and Figure 3). The designed caspases outperform the R45 and R35 random sequences.

Bottom Line: The results confirm and generalize our earlier study of SH2 and SH3 domains.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Biochimie (CNRS UMR7654), Department of Biology, Ecole Polytechnique, Palaiseau, France.

ABSTRACT

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.

Show MeSH