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Enhancing Homology Modeling for Structural Genomics

Explore the challenges and advancements in homology modeling for structural genomics. Discuss the role of comparative protein structure modeling in protein function assignment and evolutionary insights. Address current limitations, models quality, and the need for improvement. Delve into homology modeling pipelines and questions for the modeling community.

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Enhancing Homology Modeling for Structural Genomics

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  1. Topic 3: Structural Genomics and Models Contributors: S.K. Burley, A. Fiser, A. Godzik, A. Joachimiak, J. Markley, G. Montelione, C. Orengo, A. Sali, and M. Sauder Discussion Leader: Stephen K. Burley Workshop on Biological Macromolecular Structure Models RCSB PDB • Piscataway, NJ • November 19-20, 2005

  2. Role of Comparative Protein Structure Modeling in Structural Genomics

  3. Protein Structure Initiative 2: Need for Large-Scale Homology Modeling • PSI-2 will yield 3,000-4,000 protein structures, most at course granularity • Each structure will represent a large number of sequence homologues • Homology modeling must provide “useful” models for distant (15-30%) sequence homologuesprotein function assignment and evolutionary insights • Models should guide functional characterization • Models must be readily accessible • Models must be subject to rigorous peer review

  4. Issues Addressed in Contributed Slides • Current limitations of homology modeling • Role of homology modeling in target selection/execution • Role of homology modeling in structure determination • Homology modeling pipelines

  5. Current Limitations of Homology Modeling • Input from • Joachimiak--MCSG • Sali--NYSGXRC

  6. Issues with Homology Modeling for Structural Genomics • Models for distant (15-30%) homologues are poor quality • For very large families only small fraction of sequences can be reliably modeled (<10%) • Modeling must guide target selection in fine coverage of protein families • Domain parsing needs improvement • We should be able to model multi-domain proteins from structures of individual domains • We should be able to model side chains and important structural and functional features that currently are difficult to assign and predict correctly • We need methods to predict unusual features and departures from the structure that is used for modelling • Modelling loop and high B factor regions needs improvement

  7. Scope for further improvement (significant e-value, bad model score) Good Models <30% seq.id Good Models >30% seq.id. Only 363 bad-models ≥30% sequence identity. Models Based on NYSGXRC Target Structures Good Models: E-Value ≤ 1.0e-4 GAScore ≥ 0.7

  8. Questions for Homology Modeling Community • Should models be stored in archives or calculated “on the fly”? • Should models from pipeline approaches be centrally accessible? • Should the output of pipeline approaches be made interoperable with the PDB? • Should there be a publicly available model database for storage of modeling results to facilitate peer review? • Should models currently on deposit in the PDB be moved elsewhere? If so, where?

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