791_ak_lecture6

791_ak_lecture6 - 7.91 Amy Keating Ab Initio Structure...

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Ab Initio Structure Prediction Protein Design 7.91 Amy Keating
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Ab initio prediction Ab initio = “from the beginning”; in strictest sense uses first principles, not information about other protein structures In practice, all methods rely on empirical observations about other structures Force fields – Knowledge-based scoring functions –T ra in ing se ts
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Approaches to ab initio folding Full MD with explicit solvation (e.g. IBM Blue Gene) – VERY expensive –M a y n o t w o r k Reduced complexity models No side chains (sometimes no main chain atoms either!) Reduced degrees of freedom
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ROSETTA - the most successful approach to ab initio prediction David Baker, U. Washington, Seattle Based on the idea that the possible conformations of any short peptide fragment (3-9 residues) are well- represented by the structures it is observed to adopt in the pdb Generate a library of different possible structures for each sequence segment Search the possible combinations of these for ones that are protein-like by various criteria
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ROSETTA fragment libraries Remove all homologs of the protein to be modeled (>25% sequence identity) For each 9 residue segment in the target, use sequence similarity and secondary structure similarity (compare predicted secondary stucture for target to fragment secondary structure) to select ~25 fragments Because secondary structure is influenced by tertiary structure, ensure that the fragments span different secondary structures The extent to which the fragments cluster around a consensus structure is correlated with how good a model the fragment is likely to be for the target LSERTVARS
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ROSETTA search algorithm Monte Carlo/Simulated Annealing • Structures are assembled from fragments by: – Begin with a fully extended chain – Randomly replace the conformation of one 9 residue segment with the conformation of one of its neighbors in the library – Evaluate the move: Accept or reject based on an energy function – Make another random move… – After a prescribed number of cycles, switch to 3- residue fragment moves
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ROSETTA scoring function P ( structure | sequence ) = P ( structure ) × P ( sequence | structure ) P ( sequence ) sequence is constant need to estimate for decoys built from fragments Main contributions to P(structure) - secondary structure packing (e.g. ensure β -strands form β -sheets) -VdW pack
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Native-like structures have characteristic secondary structure packing Example: b-strand dipeptide vector
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791_ak_lecture6 - 7.91 Amy Keating Ab Initio Structure...

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