Journal Club

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Journal Club
Presented by Shouyong Peng May 27, 2005
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Why Study Abeta16-22 Peptide Aggregation?

• Small peptides are well suited as model systems
  for probing the mechanisms of aggregation and
  fibril formation.

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What do They do?

• Investigate the formation and properties of
  Abeta16-22 oligomers by
• unbiased Monte Carlo simulations of systems with
  up to SIX chains,
• using a sequence-based atomic model with an
  effective potential based on hydrogen bonds and
  hydrophobic attractions
• (no explicit water molecules)

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Systems

• Box size 35 Angstrom for three chains
• 44 Angstrom for six chains.
• corresponding to a constant peptide
  concentration
• Periodic boundary condition.

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Model and Methods

• Model contains all atoms of the peptide chains,
  including hydrogen atoms.
• Variables for each amino acid
• phi
• psi
• side-chain torsion angles

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Interaction potential
Excluded-volume effect Local intrachain
potential Hydrogen-bond energy Effective
hydrophobic interaction
T300K corresponds to kT0.447
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Excluded-volume Effect
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Local intrachain potential
q Partial charge -0.20 for N, H /- 0.42 for
C,O
The inner sum represents the interaction between
the partial Charges of the backbone NH and CO
groups in one amino acid
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Hydrogen-bond energy
ehb 3.1 2.0
r HO distance alpha NHO angle beta HOC
angle
Reduce strength when involving chain ends, Which
tend to be exposed to water
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Effective hydrophobic interaction
Cij is a measure of the degree of contact
between side chains i and j fraction of
atoms in contact with other side chain
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Some Tech. details
Simulated tempering Temperature is a dynamical
variable
Study one- and three-chain systems at 8 diff.
Temperatures, ranging from 275 K to 369 K Study
the six-chain system at 9 diff.
Temperatures, ranging from 287K to 369K.

• Two different elementary moves in MC for backbone
  atoms
• Highly nonlocal pivot move for a single backbone
  torsion angle
• Semilocal method that works with upto 8 adjacent
• backbone degrees of freedom
• Sidechain angles are updated one by one.
• Rigid body translation and rotation for the whole
  chain.

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Secondary structure determination
Torsion angles for inner amin acids
Parallel or antiparallel orientation end-to-end
vectors scalar product of vectors
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Schematic HB pattern
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MC evol.
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Helix and Strand contents
Nc1 agree with klimov Nc3 not agree.
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Specific heart
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Alpha-helicl intermediates?
No sign of an obligatory alpha-helical
intermediate in their model
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3-chain system
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6-chain system
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Figure 6.
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Other peptides
Small peptide with a low overall
hydrophobicity propensity to aggregate is much
lower ? hydrophobic interaction is the
driving force for aggregation Small peptide
with a significant hydrophobicity but an uneven
distribution of it KFFAAAE predominantly
parallel beta-strand organization ? the model
is capable of generating stable parallel
beta-sheets
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Examples of low-energy structures
No single dominating free-energy minimum, But
rather a number of more or less degenerate local
minima.
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Conclusion

• In this model, Abeta16-22 peptides have a high
  propensity to self-assemble into aggregated
  structures with a high beta-strand content,
  whereas isolated peptide is mainly a random coil.
• Both parallel and anti-parallel arrangements of
  the beta-strands occur in the model, with a
  definite preference for the anti-parallel
  arrangement.
• Anti-parallel preference despite ignoring the
  Coulomb interactions. Although Coulomb
  interactions might enhance the tendency for
  peptides to form beta-sheets with an
  anti-parallel organization, their results
  strongly suggest that other factors play a
  significant role, too.
• They did not observe an absolute free-energy
  minimum, but rather several minima corresponding
  to different supramolecular structures, all
  consisting of arrangements of beta-strands.
• Apart from single beta-sheets, laminated
  multisheet structures were found near free-energy
  minima for the six-chain system.