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Using Motion Planning to Study Protein Folding Pathways

Using Motion Planning to Study Protein Folding Pathways. Susan Lin, Guang Song and Nancy M. Amato Department of Computer Science Texas A&M University http://www.cs.tamu.edu/faculty/amato/. Protein Folding.

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Using Motion Planning to Study Protein Folding Pathways

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  1. Using Motion Planning to Study Protein Folding Pathways Susan Lin, Guang Song and Nancy M. Amato Department of Computer Science Texas A&M University http://www.cs.tamu.edu/faculty/amato/

  2. Protein Folding • Protein folding is a “grand challenge” problem in biology - the deciphering of the second half of the genetic code, of pressing practical significance • Problem 1: given a protein’s amino acid sequence, predict its 3D structure, which is related to its function • Problem 2: “… use the protein’s known 3D structure to predict the kinetics and mechanism of folding”[Munoz & Eaton, PNAS’99] • Finding protein folding pathways - OUR FOCUS - will assist in understanding folding and function, and eventually may lead to prediction.

  3. PRMs for Protein Folding • Node Generation [Singh,Latombe,Brutleg 99] • randomly generate conformations (determine all atoms’ coordinates) • compute potential energy E of conformation and retain node with probability P(E): • Querying the Roadmap • Add start (extended conformation) and goal (native fold) to the roadmap • Extract smallest weight path (energetically most feasible) • Roadmap Connection • find k closest nodes to each roadmap node • calculate weight of straightline path between node pairs - weight reflects the probability of moving between nodes (the smaller the weight the lower the energy)

  4. Validating Folding Pathways Protein GB1(56 amino acids) • 1 alpha helix & 4 beta-strands Hydrogen Exchange Results first helix, and beta-4 & beta-3 Our Paths 60%: helix, beta 3-4, beta 1-2, beta 1-4 40%: helix, beta 1-2, beta 3-4, beta 1-4

  5. Protein A:Potential Energy vs. RMSD for roadmap nodes hypothetical roadmap for Protein A ‘funnel’ for RMSD< 10 A, suggests packing of secondary structure (similar potentials) start: amino acid string funnel goal: native fold

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