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Transcript
Doug Raiford Lesson 18 5/23/2017 Protein Structure Searches 1 Given a protein conformation can we find other structurally similar proteins? Might have a database of structures (like the PDB) 5/23/2017 Protein Structure Searches 2 Can do a simple RMSD to compare the two conformations Know precisely which aa’s compare to which 5/23/2017 Protein Structure Searches 3 Must map aa’s from one to aa’s in the other How might you do this? Sequence similarity MSA’s 5/23/2017 Protein Structure Searches 4 3D PSSM Sequence alignment integrated with 3D alignment Stored in profile (position specific similarity profile) Gens 1D profiles first (MSAs) Then uses a structural alignment program (SAP) to augment profiles with structural similarity 5/23/2017 Protein Structure Searches 5 Aligning secondary structures 5/23/2017 Protein Structure Searches 6 What do you think of when you hear that you will need to align two things? Dynamic programming α α α T β β β α α β β β β 5/23/2017 Protein Structure Searches 7 Three components AA similarity (substitution matrix) Local structure ▪ E.g. both aa’s members of alpha helix Solvent exposure Are the associated AA’s similar, sequence wise (i.e. both glycines)? Are they both in a similar local structure? Are they both buried or both exposed to solvent? 5/23/2017 Protein Structure Searches 8 SAP (structure alignment) allows a profile to be influenced by secondary structure Useful to 3D PSSM in that threading decisions (which aa’s match to a profile) Homology based protein conformation enhanced by making better decisions on where to insert gaps/varying length loops 5/23/2017 Protein Structure Searches 9 PFAM Have Markov Models for protein families Sequences that match models have high probability of matching conformation Even though not comparing structures (query to target) are matching a sequence to its most probable structure HMMR 5/23/2017 Protein Structure Searches 10 Can’t really align How else might it work? 5/23/2017 Protein Structure Searches 11 How might two distance matrices look? All pair wise distances from each aa to all other aa’s If identical proteins the matrices would be almost identical Low distance region if hair pin (antiparallel) Low distance region in matrix if parallel 5/23/2017 Protein Structure Searches 12 Find optimum set of similar sub-structures Even if in different 1D locations Find amino acid equivalence Once have equivalence can easily compare structure similarity E.g. with RMSD 5/23/2017 Protein Structure Searches 13 Break matrix into a bunch of overlapping submatrices Do an all pair wise comparison Sub-matrices are merged that naturally extend Must find pairings of submatrices that yield best overall score 1 2 3 4 5 6 7 1 2 3 4 5 1 2 3 4 5 6 1 7 2 6 7 3 4 5 6 7 5/23/2017 Protein Structure Searches 14 Monte Carlo approach Randomly generate pairings Calculate overall similarity Multiple solutions in parallel Slowly improve each by randomly altering pairings (like a random search) Have some probability of keeping a solution that is worse than previous 1 2 3 4 5 6 7 1 2 3 4 5 1 2 3 4 5 6 1 7 2 6 7 3 4 5 6 7 5/23/2017 Protein Structure Searches 15 Can determine similarity How? 5/23/2017 Protein Structure Searches 16 Must perturb XYZ (translation), pitch, and yaw (rotation) of one of the proteins minimizing RMSD Like linear regression Can’t do until know which aa’s are associated 5/23/2017 Protein Structure Searches 17 Some numeric methods start by fixing between 2 and 4 amino acids Some short cuts Center of gravity is the average of all vectors Translate ▪ ave(p1) – ave(p2) Singular value decomposition to rotate (Like Eivenvectors) 5/23/2017 Protein Structure Searches 18 5/23/2017 Protein Structure Searches 19 Requires double dynamic programming If nxm matrix then n times m α α α T α α α T α α α T α α α α T α α αα α β αα β β β different matrices generated pinning return path to each aa pair Used to generate a position specific scoring which is then used in aa similarity scoring Reduces the constraint that two particular aa’s are equivalent 5/23/2017 Protein Structure Searches α α α T α α β 20