CE-Symm, protein symmetry, and the evolution of protein folds

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Detection and analysis of symmetry in protein structures using the algorithm CE-Symm. Protodomains and the evolution of protein folds by duplication–fusion. Presentation for Pharm Rounds at the Skaggs …

Detection and analysis of symmetry in protein structures using the algorithm CE-Symm. Protodomains and the evolution of protein folds by duplication–fusion. Presentation for Pharm Rounds at the Skaggs School of Pharmacy at the University of California, San Diego.

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  • 1. The evolution of symmetry in protein fold space Presenter: Douglas Myers-Turnbull undergraduate student, bioinformatics Systematic detection of internal symmetry in proteins using CE-Symm Douglas Myers-Turnbulla, Spencer E. Blivenb, Peter W. Rosec, Zaid K. Azidd, Philippe Youkharibachee, Philip E. Bournef,*, Andreas Prlicc,* Journal of Molecular Biology, under second-pass review.
  • 2. Symmetry is common PDB IDs from left to right: 1VYM, 3HDP, 1G62, 1U6D, 3DDV
  • 3. Why is symmetry so common?  Enzymatic function
  • 4. Why is symmetry so common?  Enzymatic function  Lowest energy state
  • 5. Why is symmetry so common?  Enzymatic function  Lowest energy state  Fewest kinetic barriers
  • 6. Why is symmetry so common?  Enzymatic function  Lowest energy state  Fewest kinetic barriers in folding Easier to evolve complex structures from simple building blocks
  • 7. The evolution of symmetry in a β-trefoil
  • 8. Building blocks of domains Modular Evolution and the Origins of Symmetry: “…symmetric protein structures can be constructed from a set of basic ‘building blocks’ or subdomain modules.”
  • 9. What is a protodomain?  A building block for domains
  • 10. What is a protodomain?  A building block for domains  A subdomain that occurs across distant folds
  • 11. What is a protodomain?  A building block for domains  A subdomain that occurs across distant folds  Unlikely to have arisen by chance
  • 12. Algorithms that detect symmetry  sequence-based methods Ex: DAVROS [Taylor et. al.]  angle-based methods Ex: Swelfe [Abraham et. al.]  methods based on secondary structure Ex: GANGSTA+ [Guerler et. al.]  truly structural methods Ex: SymD [Kim et. al.]
  • 13. CE-Symm  Align a structure against itself
  • 14. CE-Symm  Align a structure against itself  Use Combinatorial Extension
  • 15. A large benchmark set  1,007 distinct SCOP superfamilies
  • 16. A large benchmark set  1,007 distinct SCOP superfamilies  manually determined symmetry
  • 17. CE-Symm is very accurate
  • 18. Structural classification of proteins  SCOP: class→fold→superfamily→family→domain
  • 19. Structural classification of proteins  SCOP: class→fold→superfamily→family→domain  Different superfamilies of the same fold often have substantial differences in structure
  • 20. Normalization by superfamilies  Normalize by number of domains per superfamily
  • 21. Normalization by superfamilies  Normalize by number of domains per superfamily  A superfamily is symmetric if more than half of its domains are symmetric.
  • 22. A census of symmetry SCOP class number of SFs % symmetric (SFs) α 503 18.5% β 354 24.6% α/β 244 16.8% α+β 549 14.3% membrane 108 23.8% overall 1824 18.0% Complete results available at: http://source.rcsb.org
  • 23. A census of symmetry SCOP class number of SFs % symmetric (SFs) α 503 18.5% β 354 24.6% α/β 244 16.8% α+β 549 14.3% membrane 108 23.8% overall 1824 18.0% Complete results available at: http://source.rcsb.org
  • 24. A census of symmetry SCOP class number of SFs % symmetric (SFs) α 503 18.5% β 354 24.6% α/β 244 16.8% α+β 549 14.3% membrane 108 23.8% overall 1824 18.0% Complete results available at: http://source.rcsb.org
  • 25. Symmetry and evolution  How can we use this to learn about evolution?
  • 26. Is this domain symmetric? PDB ID: 3DDV. Zhang, R. et. al.
  • 27. CE-Symm says it’s symmetric
  • 28. Did we find a protodomain? A protodomain?
  • 29. Search for matching domains
  • 30. A hit against another domain
  • 31. It’s a β-propeller blade! PDB ID: 1SHY. Stamos, J. et. al.
  • 32. It’s a β-propeller blade! PDB ID: 1SHY. Stamos, J. et. al.
  • 33. Identifying protodomains systematically 1. Identify subdomains of symmetric structures with CE-Symm
  • 34. Identifying protodomains systematically 1. Identify subdomains of symmetric structures with CE-Symm 2. Identify hits against other domains
  • 35. Identifying protodomains systematically 1. Identify subdomains of symmetric structures with CE-Symm 2. Identify hits against other domains 3. Derive a non-redundant set of protodomains
  • 36. CE-Symm is on the web http://source.rcsb.org
  • 37. Acknowledgments  Dr. Andreas Prlic, San Diego Supercomputer Center  Spencer Bliven, Bioinformatics and Systems Biology  Dr. Peter Rose, Skaggs School of Pharmacy  Zaid Aziz, Chemistry and Biochemistry  Dr. Philippe Youkharibache, Life Sciences R&D  Dr. Phil Bourne, Skaggs School of Pharmacy
  • 38. CE-Symm 1. Disable main diagonal (δ = 20)
  • 39. CE-Symm 1. Disable main diagonal (δ = 20) 2. Duplicate matrix
  • 40. CE-Symm 1. Disable main diagonal (δ = 20) 2. Duplicate matrix 3. Superimpose matrices
  • 41. Current limitation: order-detection  CE-Symm sometimes reports the wrong order
  • 42. Two methods for order-detection  Method 1: apply alignment repeatedly until the composition becomes approximately the identity  Method 2: identify the lowest difference ε(θ):
  • 43. Most symmetric architectures are old
  • 44. Types of symmetry in the benchmark
  • 45. Some functions are related to symmetry
  • 46. CE-Symm identifies symmetric folds id fold CE-Symm (%) SymD (%) GANGSTA (%) d.58 Ferredoxin-like 72 19 23 b.1 Immunoglobulin-like 61 8.9 8.4 b.42 Beta-Trefoil 97 100 56 a.24 Four-helical bundle 73 51 25 d.131 DNA clamp 100 91 64 b.69 7-bladed beta propeller 100 100 37 c.1 TIM beta/alpha barrel 87 83 3.7 b.11 Gamma-Crystallin-like 92 75 83
  • 47. A stable synthetic β-trefoil  Native function was lost
  • 48. A synthetic adiponectin trimer  Native function increased!
  • 49. Symmetry is commonplace  Quaternary symmetry  Symmetry around active sites PDB ID: 3HDP. Satyanarayana, L et. al.
  • 50. Symmetry is commonplace  Quaternary symmetry  Symmetry around active sites PDB ID: 2GZL. Crane, C.M. et. al.
  • 51. Symmetry is commonplace  Quaternary symmetry  Symmetry around active sites  Nested symmetry PDB ID: 2GG6. Funke, T. et. al.
  • 52. Symmetry is commonplace  Quaternary symmetry  Symmetry around active sites  Nested symmetry PDB ID: 2GG6. Funke, T. et. al.