Recursive domains in proteins

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Recursive domains in proteins

• Teresa Przytycka
• NCBI, NIH
• Joint work with G.Rose Raj Srinivasan JHU

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Domain Polypeptide chain (or a part of it) that
can independently fold into stable tertiary
structure (Baranden Tooze Introduction to
Protein Structure)
Two-domain protein.
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The 3D structure of a protein domain can be
described as a compact arrangement of secondary
structures
Alpha helix
Beta strand
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These arrangements are far from random
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There are not so many of them
PDB contains about 17000 structures and less than
1000 different folds.
Proportion of "new folds" (light blue) and "old
folds" (orange) for a given year.
(fold fold domain)
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Possible sources of restricted number of folds

• Evolutionary history.
• Given enough time would domains look more
  random?
• Existence of general restrictions/rules which
  render some (compact) arrangements of secondary
  structures non-feasible.
• Can real protein domains be seen as sentences in
  a language, which can be generated by an
  underlying grammar?

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Can protein domains be described using a set of
folding rules?

• We restrict our attention to all beta domains
• they admit variety of topologies
• they are difficult to predict from sequence

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Understanding b-folds

• Patterns in b-sheets
• Richardson 1977
• folding rules for b-sheets
• Zhang and Kim 2000
• Hydrogen bonding pattern
• Polypeptide chain seems to avoid complications
• Properties of b-sandwiches
• Woolfson D. N., Evans P. A., Hutchinson E. G.,
  and Thornton J. M. 1993

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Expectations for good folding rules

• We need to look at fold properties that occur in
  non-homologous proteins.
• Preferably The provide a model for the folding
  process.

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Super-secondary structures as precursors of
folding rules

• Super-secondary structure frequently occurring
  arrangements of a small number of secondary
  structures
• The occurrences of super-secondary structures in
  unrelated families supports possibility of their
  independent formation.

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Example 1 Hairpin
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b-b-b-unit
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Example 2 Greek key and suggested folding
pathway for it
Folding pathway for Greek key proposed by
Ptitsyn.
Pattern from a Greek vase
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Two level of folding rules

• Primitive folding rules based on super
  secondary structures
• Closure operation allows for hierarchical
  application of the primitive rules

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supersecondary structures -primitive folding rules
hairpin
Hairpin rule
Bridge
Greek key
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Direct wind
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Closure-composite rules

• Super-secondary structures are composed of
  secondary structures that are neighboring in the
  chain sequence
• However from the presence of a super-secondary
  structure, like a hairpin, in a protein structure
  follows that residues that are non consecutive
  become neighboring in space.

Closure - short cut in the sequence due to a
folding rule
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Example 1applying folding rules to jelly roll
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Recursive domains

• Recursive domain is a part of a protein fold
  that can be generated using folding rules
  supported with the closure operation.
• A protein that can be fully generated using
  folding rules has one recursive domain.

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Examples

• Example 1
• Example 2
• Example 3
• Example 4

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Recursive domains

• Recursive domain is a part of a protein fold
  that can be generated using folding rules
  supported with the closure operation.
• A protein that can be fully generated using
  folding rules has one recursive domain.

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Graph theoretical tools and recursive domains

• Fold graph Vertices strands Edges two
  types
• Neighbor edges directed edges between strands
  that are neighbors in chain or vie the closure
  operation.
• Domain edge edges between stands used in the
  same folding rule
• Recursive domains connected component of the
  fold graph without neighbor edges.

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Partition into recursive components for small
(lt10 strands) proteins
Can the rules generate all known folds?
Comparison with the partition for computer
generated set of all possible 8-strand sandwiches
Control
Protein data
One recursive fold
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Offenders
Hedhehog intein domain
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Given a fold, is there a unique sequence of
folding steps leading to it?

• Usually no.

Usually there alternative sequences of folding
steps leading to a construction of the same
domain. Do such alternative folding sequences
correspond to alternative folding pathways?
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Are the rules complete?
Probably not. e.g. For propeller, each blade
is in one recursive domain but we do not have a
rule that will put the blades together.
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Conclusions We are getting some idea how things
work...
It is so nice outside. It would be nice to take
the dog for a walk!
Nice dog walk
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Conclusions

• Protein folds can be described by simple folding
  rules.
• The folding rules capture at least some aspects
  of fold simplicity and regularity.
• The sequence of folding steps leading to a given
  fold is usually not unique.
• The folding rules generate protein-like
  structures.

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Future directions

• Can folding rules guide fold prediction?
• Would hierarchical description of a fold provided
  by folding rules be useful for fold
  classification / comparison ?
• Adding statistical evaluation of a recursive
  domain.

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Acknowledgments

• George Rose
• Raj Srinivasen
• Rohit Pappu
• Venk Murthy

NIH, K01 grant