lecture17_S2009

lecture17_S2009 - Super-Secondary Structure Prediction of...

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Super-Secondary Structure Prediction of Transmembrane β -barrel Proteins (Part II) Jérôme Waldispühl, Charles W. O’Donnell 18.417: Foundation of Computational Structural Biology April 14, 2009
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2/39 Primary Goal: Protein structure s prediction from AA sequence for conserved β –sheet folds Predict the ensemble of possible structures instead of a single minimum structure Accounts for multiple conformations Predicts macroscopic experimental properties Boltzmann Partition Function estimation stochastically describes conformational space (folding landscape) Works well for predicting super-secondary structure ensembles of Transmembrane -barrel (TMB) proteins 50,000 ft overview Picture: Mukamel Group, UCI
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3/39 Transmembrane β -barrel proteins TMBs: Found in outer-membranes Important for signaling, drugs, etc TM barrel fold highly conserved across species, but high sequence variability (Schultz’00) TMBs undergo conformational changes in vivo (Tamm’04)
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4/39 partiFold approach 2-tape S-attribute grammar defines family of abstract templates Amino acid pair potentials (Sippl’90) sum to define “energy” of conformations Knowledge-based statistical potentials Energy model can easily be redefined Compute all possible structures
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5/39 Boltzmann ensembles Boltzmann Partition Function Encodes statistical mechanical properties of system: Allows: Sample structures from ensemble Predict B-values Find residue-residue contact probability (and entropy) Finding Q(s) from 3D structural model ˠ Intractable from 2D lattice ˠ Tractable (Istrail’00) (eg. unrolled barrel)
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6/39 Results: multiple viable structures Clustering gives multiple compact clusters of conformations One cluster matches x-ray crystal structure well (sens/ppv > 60-70%) ompX Residue index But other clusters also well represented Sample structures, identify substructure probabilities
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7/39 Contact probability profile P cp (i) Frequency of β –strand pairing per residue Debye-Waller factor ( B-value ) in x-ray crystal structures Indicates uncertainty or disorder in crystal Higher values of P cp (i) and B-value indicate more flexible regions (eg. loops) Results: predicting B-value Residue index ompX
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8/39 Results: per-AA contact prediction Predict probability of 2 residues contacting in ensemble - p(i,j) Can be used to help reconstruct 3D models (Grana’05, Punta’05) Probability p c Percent of predicted contacts found in x-ray struct # contacts in x-ray struct Accuracy All contacts where p(i,j) > p c Accuracy % ompX
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9/39 Details: Modeling with grammars 2-tape grammar model TMB protein containing only β –strands and loops/random-coils
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10/39 TMB represented by a 2-tape word defining barrel β -strand contacts Considers membrane- and channel-facing residues Details: Modeling with grammars
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11/39 Strand inclination (shear) handled by Extensions Example: Details: Modeling with grammars Left pairing Right pairing
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lecture17_S2009 - Super-Secondary Structure Prediction of...

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