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The evolution of symmetry in protein
fold space
Presenter: Douglas Myers-Turnbull
undergraduate student, bioinformatics
Sy...
Symmetry is common
PDB IDs from left to right:
1VYM, 3HDP, 1G62, 1U6D, 3DDV
Why is symmetry so common?
 Enzymatic function
Why is symmetry so common?
 Enzymatic function
 Lowest energy state
Why is symmetry so common?
 Enzymatic function
 Lowest energy state
 Fewest kinetic barriers
Why is symmetry so common?
 Enzymatic function
 Lowest energy state
 Fewest kinetic barriers in folding
Easier to evolv...
The evolution of symmetry in a β-trefoil
Building blocks of domains
Modular Evolution and the Origins of Symmetry:
“…symmetric protein structures can be constructe...
What is a protodomain?
 A building block for domains
What is a protodomain?
 A building block for domains
 A subdomain that occurs across distant folds
What is a protodomain?
 A building block for domains
 A subdomain that occurs across distant folds
 Unlikely to have ar...
Algorithms that detect symmetry
 sequence-based methods
Ex: DAVROS [Taylor et. al.]
 angle-based methods
Ex: Swelfe [Abr...
CE-Symm
 Align a structure against itself
CE-Symm
 Align a structure against itself
 Use Combinatorial Extension
A large benchmark set
 1,007 distinct SCOP superfamilies
A large benchmark set
 1,007 distinct SCOP superfamilies
 manually determined symmetry
CE-Symm is very accurate
Structural classification of proteins
 SCOP: class→fold→superfamily→family→domain
Structural classification of proteins
 SCOP: class→fold→superfamily→family→domain
 Different superfamilies of the same f...
Normalization by superfamilies
 Normalize by number of domains per superfamily
Normalization by superfamilies
 Normalize by number of domains per superfamily
 A superfamily is symmetric if more than ...
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%
membra...
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%
membra...
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%
membra...
Symmetry and evolution
 How can we use this to learn about evolution?
Is this domain symmetric?
PDB ID: 3DDV. Zhang, R. et. al.
CE-Symm says it’s symmetric
Did we find a protodomain?
A protodomain?
Search for matching domains
A hit against another domain
It’s a β-propeller blade!
PDB ID: 1SHY. Stamos, J. et. al.
It’s a β-propeller blade!
PDB ID: 1SHY. Stamos, J. et. al.
Identifying protodomains systematically
1. Identify subdomains of symmetric structures with
CE-Symm
Identifying protodomains systematically
1. Identify subdomains of symmetric structures with
CE-Symm
2. Identify hits again...
Identifying protodomains systematically
1. Identify subdomains of symmetric structures with
CE-Symm
2. Identify hits again...
CE-Symm is on the web
http://source.rcsb.org
Acknowledgments
 Dr. Andreas Prlic, San Diego Supercomputer Center
 Spencer Bliven, Bioinformatics and Systems Biology
...
CE-Symm
1. Disable main diagonal (δ = 20)
CE-Symm
1. Disable main diagonal (δ = 20)
2. Duplicate matrix
CE-Symm
1. Disable main diagonal (δ = 20)
2. Duplicate matrix
3. Superimpose matrices
Current limitation: order-detection
 CE-Symm sometimes reports the wrong order
Two methods for order-detection
 Method 1: apply alignment repeatedly until the
composition becomes approximately the ide...
Most symmetric architectures are old
Types of symmetry in the benchmark
Some functions are related to symmetry
CE-Symm identifies symmetric folds
id fold CE-Symm (%) SymD (%) GANGSTA (%)
d.58 Ferredoxin-like 72 19 23
b.1 Immunoglobul...
A stable synthetic β-trefoil
 Native function was lost
A synthetic adiponectin trimer
 Native function increased!
Symmetry is commonplace
 Quaternary symmetry
 Symmetry around active sites
PDB ID: 3HDP. Satyanarayana, L et. al.
Symmetry is commonplace
 Quaternary symmetry
 Symmetry around active sites
PDB ID: 2GZL. Crane, C.M. et. al.
Symmetry is commonplace
 Quaternary symmetry
 Symmetry around active sites
 Nested symmetry
PDB ID: 2GG6. Funke, T. et....
Symmetry is commonplace
 Quaternary symmetry
 Symmetry around active sites
 Nested symmetry
PDB ID: 2GG6. Funke, T. et....
CE-Symm, protein symmetry, and the evolution of protein folds
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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 School of Pharmacy at the University of California, San Diego.

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

  1. 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. 2. Symmetry is common PDB IDs from left to right: 1VYM, 3HDP, 1G62, 1U6D, 3DDV
  3. 3. Why is symmetry so common?  Enzymatic function
  4. 4. Why is symmetry so common?  Enzymatic function  Lowest energy state
  5. 5. Why is symmetry so common?  Enzymatic function  Lowest energy state  Fewest kinetic barriers
  6. 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. 7. The evolution of symmetry in a β-trefoil
  8. 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. 9. What is a protodomain?  A building block for domains
  10. 10. What is a protodomain?  A building block for domains  A subdomain that occurs across distant folds
  11. 11. What is a protodomain?  A building block for domains  A subdomain that occurs across distant folds  Unlikely to have arisen by chance
  12. 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. 13. CE-Symm  Align a structure against itself
  14. 14. CE-Symm  Align a structure against itself  Use Combinatorial Extension
  15. 15. A large benchmark set  1,007 distinct SCOP superfamilies
  16. 16. A large benchmark set  1,007 distinct SCOP superfamilies  manually determined symmetry
  17. 17. CE-Symm is very accurate
  18. 18. Structural classification of proteins  SCOP: class→fold→superfamily→family→domain
  19. 19. Structural classification of proteins  SCOP: class→fold→superfamily→family→domain  Different superfamilies of the same fold often have substantial differences in structure
  20. 20. Normalization by superfamilies  Normalize by number of domains per superfamily
  21. 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. 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. 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. 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. 25. Symmetry and evolution  How can we use this to learn about evolution?
  26. 26. Is this domain symmetric? PDB ID: 3DDV. Zhang, R. et. al.
  27. 27. CE-Symm says it’s symmetric
  28. 28. Did we find a protodomain? A protodomain?
  29. 29. Search for matching domains
  30. 30. A hit against another domain
  31. 31. It’s a β-propeller blade! PDB ID: 1SHY. Stamos, J. et. al.
  32. 32. It’s a β-propeller blade! PDB ID: 1SHY. Stamos, J. et. al.
  33. 33. Identifying protodomains systematically 1. Identify subdomains of symmetric structures with CE-Symm
  34. 34. Identifying protodomains systematically 1. Identify subdomains of symmetric structures with CE-Symm 2. Identify hits against other domains
  35. 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. 36. CE-Symm is on the web http://source.rcsb.org
  37. 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. 38. CE-Symm 1. Disable main diagonal (δ = 20)
  39. 39. CE-Symm 1. Disable main diagonal (δ = 20) 2. Duplicate matrix
  40. 40. CE-Symm 1. Disable main diagonal (δ = 20) 2. Duplicate matrix 3. Superimpose matrices
  41. 41. Current limitation: order-detection  CE-Symm sometimes reports the wrong order
  42. 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. 43. Most symmetric architectures are old
  44. 44. Types of symmetry in the benchmark
  45. 45. Some functions are related to symmetry
  46. 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. 47. A stable synthetic β-trefoil  Native function was lost
  48. 48. A synthetic adiponectin trimer  Native function increased!
  49. 49. Symmetry is commonplace  Quaternary symmetry  Symmetry around active sites PDB ID: 3HDP. Satyanarayana, L et. al.
  50. 50. Symmetry is commonplace  Quaternary symmetry  Symmetry around active sites PDB ID: 2GZL. Crane, C.M. et. al.
  51. 51. Symmetry is commonplace  Quaternary symmetry  Symmetry around active sites  Nested symmetry PDB ID: 2GG6. Funke, T. et. al.
  52. 52. Symmetry is commonplace  Quaternary symmetry  Symmetry around active sites  Nested symmetry PDB ID: 2GG6. Funke, T. et. al.

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