Domains

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Domains

• typical size 100-200 amino acids
• mean160 residues
• balance surface area to volume (hydrophobics in
  core)
• modularity, though insertions are possible
• a, b, ab, a/b (wound bab, parallel strands)
• classic folds globins, immunoglobulins,
  TIM-barrels, NBDs
• beta-sandwiches/clamshells, helix-bundles
• helical coiled-coils (collagen, lambda repressor)
• beta-barrels, beta-propellers

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• domain insertions
• (the strange case of malate synthase...)

active site in mouth of beta-barrel
C-terminal cap
see 4 domains on CATH page http//www.cathdb.info
/chain/1n8wA
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• How small can a protein be and still have
  structure?
• no hydrophobic core
• glucagon (30 res, a-helix) dis-ordered in
  solution
• unraveling, conformational sampling
• NMR studies of peptides?
• 10-aa SCF recognition peptide
• disorder of p53 fragment in soln by NMR
• on the contrary, 17-residue fragment from
  N-terminal domain of ubiquitin folds into
  beta-hairpin on its own
• Zarella et al, Protein Science, 1999

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Structure Superposition Algorithms

• least-squares
• Aij ?PkiQkj product over 2 sets of coords, P
  and Q
• R (AtA)1 / 2A-1 rotation that minimizes RMSD
• assumes translated to centers-of-mass
• Kabsch rotation algorithm (1976, Acta) (equiv.
  to SVD)
• MacKay (1984, Acta) quaternions (solve linear
  system)
• SSAP (Orengo and Taylor)
• dynamic programming to minimize inter-molecular
  distance vectors between Cb atoms
• pairs must be known a priori

let mij be eigenvalues and aij be eigenvectors of
RTR
Lij are Lagrange multipliers. determine by
solving
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• DALI (Holm and Sander)
• aligns scalar distance plots
• significance z-scores z(s-m)/sgt7.0
• compare to scores from random alignments
• beware of effect of length of aligned/rejected
  shorter-gtbetter score

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• VAST (Gibrat and Bryant)
• aligns secondary structure elements
• graph theory algotrithm finds maximal clique in
  graph of consistent alignable pairs of vectors
• LOCK (Singh and Brutlag)
• hierarchical, distances SS elements
• rigid bodies cant always be aligned well
• CE (combinatorial extension ShindalyovBourne)
• identifies similar local fragments (3-5aa),
  extends them
• more tolerant of flexible regions
• SSM (Krissinel and Henrick)
• subgraph isomorphism
• must preserve topology?

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LOCK (Singh and Brutlag)
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Fold Families

• clustering
• PDBSelect and COG are based on homology only
• FSSP - based on DALI score
• SCOP manually curated (by Alexy Muzrin)
• CATH (Orengo and Thornton)
• Pfam based on HMMs (more details later)

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(beware of large-family bias when averaging over
protein database)
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Fold Recognition

• sequence alignment (homology)
• position-dependent profiles from multiple
  alignment (Gribskov, McLachlan, Eisenberg, 1987),
  scores based on sum of Dayhoff similarity over
  observed residues at each pos.
• 3D profiles
• threading
• HMMs

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• Convergence vs. Divergence

Sander and Schneider (1991) Database of
Homology-Derived Protein Structures and the
Structural Meaning of Sequence Alignment. Chothia,
C. (1993). One thousand families for the
molecular biologist.
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3D Profiles (Eisenberg et al.)

• Given that you have a sequence threaded onto a
  known structure, how well does it fit the fold?
• originally residues scored by 18 environment
  classes (Bowie, Luthy, Eisenberg, 1991)
• similarity of amino acids in model to structure
  (homology, position-dependent distribution)
• tolerance of buried vs. surface exposure
• suitability of residues in secondary structures
• residue pair potentials (likelihood of contacts
  at 4-10A radius shells) (Wilmanns and Eisenberg,
  1993)

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18 environment classes E,P1,P2,B1,B2,B2xheli
x,sheet,coil
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Threading (for Fold Recognition)

• find optimal mapping of residues in sequence to
  model
• higher computational complexity that sequence
  alignment, or can also be done by dynamic
  programming?
• Lathrop (Prot Eng, 1994 JMB, 1996) - showed that
  threading is NP-complete when non-local effects
  are taken into account (reduction to 3SAT)
• fold evaluation
• 3D profiles
• packing (steric conflicts, voids)
• energy (molecular mechanics force field)
• statistical (side-chain contacts, Sippl)
• PHYRE (Sternberg) 3D-PSSM search
• THREADER (David Jones) dynamic programming
• RAPTOR (Jinbo Xu) integer programming
  (constraints)

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Pfam, Hidden Markov Models (HMMs) (Sonnhammer,
Eddy, and Durbin, 1997)
Viterbi algorithm (forward/backward) training
maximum likelihood, EM
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HMM for 628 globins (lines indicate
most frequently- used transitions)
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Linkers
1BEF - protease
1YBA PDGH tetramer

• definition
• do not pack against well-defined domains (lack
  contact not necessarily exposed, though)
• cant count on sequence between known domains
• flexible, lack regular secondary structure (not
  always coil helical linkers exist)
• rich in Pro, Ala, charged residues lack of Gly
• George and Heringa (2002)
• Bae, Mallick, Elsik (2005) HMM (accuracy 67)

4FAB - immunoglobulin
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• Tanaka, Yokayama, Kuroda (2006) length
  dependence
• significant frequency deviations were observed
  for glycine, proline, and aspartic acid in short
  linker and nonlinker loops, whereas deviations
  were observed for aspartic acid, proline,
  asparagine, and lysine in long linker and
  nonlinker loops.

all fragments length lt 9 aa length gt 9 aa

• DomCut (Suyama Ohara, 2003)
• uses differences in amino acid composition
  between the intra- and interdomain regions to
  predict domain boundaries
• Armadillo (Dumontier et al., 2005)
• local smoothing of aa propensity index by FFT
  calculates Z-score