Protein Dynamics

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Protein Dynamics

• Hierarchical conformational substates.

Biocomputing does it all!
A.H.Juffer The University of Oulu Finland-Suomi
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Articles

• Schultz, Curr. Op. Struct. Biol., 1, 883-888,
  1991.
• Hayward and Go, Annu.Rev. Phys. Chem., 46,
  223-250, 1995.
• Kitao et al., Proteins. Struct. Func. Gen., 33,
  496-517, 1998.
• Kitao et al., Curr. Op. Struct. Biol., 9,
  164-169, 1999.

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Topics

• Collective or concerted motions in protein
  structures.
• Energy landscape of a native protein
  Jumping-Among-Minima model (JAM).
• Protein free energy and entropy.

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Dynamics General

• Dynamics and function are related.
• High and low frequency motions low frequency
  motions are important for function.
• Domain motions Important for function of
  transport proteins, protein regulation, enzyme
  catalysis.
• Domain motion can be seen as a semi-rigid body
  motion ?A protein is essentially a collection of
  connected rigid bodies.
• Detection of such domains is not trivial.

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Dynamics frequency scale
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Frequency scale of proteins

• Computer simulation versus experiment.
• Molecular dynamics versus neutron scattering.

Hinsen and Kneller, J. Chem. Phys., 111,
10766-10769, 1999.
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Protein energy landscape
Energy
States
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Four questions

• Are conformational substates mutually similar?
• How are conformational substates distributed in
  the multi-dimensional conformational space?
• Are conformational substates hierarchical?
• How does the subspace, which contains
  conformational substates, evolves as function of
  time?

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Methods

• Normal mode analysis of protein in vacuum.
• Principle component analysis of the protein in
  water (essential dynamics).
• New method JAM model separates the motions into
  intra-substate and inter-substate motions
  (catchment regions)

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What is a catchment region?

• The whole of the native-state conformations
  (substates) is grouped into catchment regions,
  each containing one energy minimum.
• JAM(I) model the local energy landscape is the
  same in each catchment region harmonic
  approximation.
• JAM(R) model substates correspond to rotamer
  states (dihedral angles) Space?subspaces
  ?protein rotamer states (all dihedral angles in
  the same state)?catchment regions.

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Free energy profiles

• Multiply-hierarchical modes, energy barriers
• singly-hierarchical modes.
• Harmonic modes.

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Principal mode category
First 300 modes are termed anharmonic modes.
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Main conclusions

• Solvent molecules around protein move together
  with protein.
• Local energy surfaces of conformational substates
  are nearly harmonic and mutually similar.
• Subspace spanned by multiply-hierarchical modes
  (essential subspace) is time dependent, whereas
  the subspace spanned by all anharmonic modes is
  time independent.
• Anharmonic modes only a few procent of all modes
  (for lysozyme, 4.5).

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Main conclusions

• Inter-substate motions occur in a
  small-dimensional conformational subspace.
• This subspace is spanned by the multiply- and
  singly-hierarchical modes.
• Two levels of inter-substate motions fast (1-5
  ps) and slow (gt 200 ps.)
• Functional importance of hierarchical modes.