Defrosting the frozen approximation: PROSPECTOR--a new approach to threading

Area of Science:

• Computational Biology
• Bioinformatics
• Structural Bioinformatics

Background:

• Protein structure prediction is crucial for understanding protein function.
• Threading methods align sequences to known structures to infer models.
• Improving the accuracy of template-based modeling remains a key challenge.

Purpose of the Study:

• To introduce PROSPECTOR, a new hierarchical threading approach for protein structure prediction.
• To enhance the accuracy of probe-template alignment and pair interaction evaluation.
• To develop a web server for public access to the PROSPECTOR method.

Main Methods:

• PROSPECTOR utilizes sequence profiles (close and distant sets) for initial probe-template alignment.
• A hierarchical scoring function combines sequence, secondary structure, and pair interaction profiles.
• A protein-specific pair potential is constructed from consensus contacts in top-scoring templates.

Main Results:

• PROSPECTOR1 correctly identified 59 of 68 pairs in the top position on the Fischer database.
• PROSPECTOR2, incorporating protein-specific pair potentials, improved identification to 61 of 68 pairs.
• On a second database, PROSPECTOR1 and PROSPECTOR2 placed 18 and 17 structures in the top position, respectively.

Conclusions:

• The hierarchical threading approach, particularly with protein-specific pair potentials, significantly enhances the accuracy of protein structure prediction.
• Improved Z-scores for pair interactions increase the specificity of probe-template matches.
• A web server is available for the academic community to utilize the PROSPECTOR method.