local flexibility aids protein multiple structure alignment matt menke bonnie berger lenore cowen
DESCRIPTION
What Makes a Good Alignment? Geometric criteria: Good multiple structure alignments MAXIMIZE number of residues places in alignment while MINIMIZING distances between aligned residues.TRANSCRIPT
![Page 1: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/1.jpg)
Local Flexibility Aids Protein Multiple Structure Alignment
Matt Menke Bonnie BergerLenore Cowen
![Page 2: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/2.jpg)
The Protein Multiple Structure Alignment Problem
Input: The 3D coordinates of the atomic structures of k proteins
Output: A multiple sequence alignment, together with a set of rigid body transformations that superimpose the structures
![Page 3: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/3.jpg)
What Makes a Good Alignment?
Geometric criteria: Good multiple structure
alignments MAXIMIZE number of residues places in alignment while MINIMIZING distances between aligned residues.
![Page 4: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/4.jpg)
What Makes a Good Alignment?
Geometric criteria: BICRITERIA
OPTIMIZATION PROBLEM:
Place everything in the core, and residue distances are bad.
Place a single residue in the core, all distances are great!
![Page 5: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/5.jpg)
What Makes a Good Alignment?
Biological criteria: Good multiple structure
alignments align structures (and portions within structures) that are supposed to align.
![Page 6: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/6.jpg)
History of the Protein Structure Alignment Problem
• Studied as long as the better-known multiple sequence alignment problem
• Pairwise and multiple structure versions• Wikipedia has links to over 50 different
methods (programs/server/papers)• NP-hard for ever simple variants
(reference)
![Page 7: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/7.jpg)
Approaches to Structure Alignment
Contact Map Methods look for similarities in the distance matrix of each protein.
Itoh, Kazuhito and Sasai, Masaki (2006) Proc. Natl. Acad. Sci. USA 103, 7298-7303
![Page 8: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/8.jpg)
Approaches to Structure Alignment
• AFP chaining methods align all short pieces and chain together using dynamic programming
• Geometric hashing, secondary structure elements, etc.
![Page 9: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/9.jpg)
![Page 10: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/10.jpg)
The Benchmark Datasets
• Globins• Homstrad
– 1028 alignments – Each alignment contains 2-41 structures– 399 sets with > 2 structures
![Page 11: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/11.jpg)
Why Another Structure Aligner?
![Page 12: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/12.jpg)
The Benchmark Datasets
Sabmark – more distant homologySuperfamily set: – 3645 domains in 426 subsetsTwilight zone set: – 1740 domains in 209 subsetsBoth sets contain: – Between 3 and 25 structures– Decoy structures (sequence matches that
reside in different SCOP domains)
![Page 13: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/13.jpg)
Matt: Multiple Alignment with Translation and Twists
• Matt is an AFP chaining method that additionally adds flexibility in the form of geometrically impossible bends and breaks.
![Page 14: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/14.jpg)
Other work modeling flexibility
• In structure alignment: – Flexprot [Shatsky et al., 2002]– Fatcat/POSA [Ye&Godzik, 2004, 2005]
• For other reasons: – Molecular docking [Echols et al,03; Bonvin,06]– Ligand binding [Lemmen et al, 2006]– Decoy construction [Singh&Berger, 2006]
![Page 15: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/15.jpg)
Matt: Pairwise alignment algorithm
1. Align all-against-all 5-9 residue fragments
2. Assemble fragment pairs with dynamic programming, allowing “impossible” local rotations & translations (bent alignment)
3. Keeping residue correspondences, find best rigid body superimposition (unbent alignment)
![Page 16: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/16.jpg)
![Page 17: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/17.jpg)
![Page 18: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/18.jpg)
![Page 19: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/19.jpg)
Outline of the Matt Algorithm
![Page 20: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/20.jpg)
Results on Sabmark (Superfamily)
Program Name Avg. Core Size Avg. RMSD
Multiprot 68.701 1.498
Mustang 104.162 4.146
Matt 104.692 2.639
![Page 21: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/21.jpg)
Results on Sabmark (Twilight Zone)
Program Name Avg. Core Size Avg. RMSD
Multiprot 36.54 1.536
Mustang 66.833 5.035
Matt 66.967 2.916
![Page 22: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/22.jpg)
![Page 23: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/23.jpg)
![Page 24: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/24.jpg)
Sabmark Decoy Set
• For each SCOP superfamily, positive examples of the fold, and negative examples that are – Random examples from a different
superfamily– Examples from a different superfamily that are
nonetheless good BLAST hits
![Page 25: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/25.jpg)
![Page 26: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/26.jpg)
On the Web
• Matt source code and Windows binaries can be downloaded from: http://matt.cs.tufts.edu or http://groups.csail.mit.edu/cb/matt/
• Licensed under GPL 2.0; talk to us for commercial resale licensing.
• Accepts PDB files; outputs bent and unbent alignments in FASTA, PDB and RASMOL format.
• Matt paper: “M. Menke, B. Berger, L. Cowen, "Matt: Local Flexibility Aids Protein Multiple Structure Alignment", PLOS Computational Biology, Vol. 4, No 1., 2008.
![Page 27: Local Flexibility Aids Protein Multiple Structure Alignment Matt Menke Bonnie Berger Lenore Cowen](https://reader035.vdocument.in/reader035/viewer/2022062505/5a4d1be27f8b9ab0599e06f7/html5/thumbnails/27.jpg)
Acknowledgements
• National Science Foundation• National Institutes of Health