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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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The evolution of symmetry in protein
fold space
Presenter: Douglas Myers-Turnbull
undergraduate student, bioinformatics
Systematic detection of internal symmetry in proteins
using CE-SymmDouglas 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.
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 evolve complex structures from simple
building blocks
The evolution of symmetry in a β-trefoil
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.”
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 arisen by chance
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.]
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 fold often have
substantial differences in structure
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 half of its
domains are symmetric.
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
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
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
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 against other domains
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
CE-Symm is on the web
http://source.rcsb.org
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
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 identity
Method 2: identify the lowest difference ε(θ):
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 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
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. al.
Symmetry is commonplace
Quaternary symmetry
Symmetry around active sites
Nested symmetry
PDB ID: 2GG6. Funke, T. et. al.
