Protein aggregation simulations with ProFASi
Simulation of peptide aggregation poses a slightly different set of challenges than the
simulation of protein folding. Typically one deals with a larger number of atoms and
degrees of freedom in the system. The conformation space that the simulation must
explore not only includes forms taken by the individual chains, but also the relative
arrangement of different chains. Despite such increase in complexity, at least for
small peptides, this is a manageable problem, because the peptides themselves are
incapable of complex structures on their own. Simulation of
a single protein of 70 residues is a more difficult problem than that of 10 copies
of a 7 residue peptide. An oligomeric structure consisting of, for instance, 6 chains
has a large combinatorial advantage compared to a similar structure made by 42 residues of
a fictitious 70 residue chain. If one exchanges the coordinates of two chains in the
oligomer, one gets an identical structure. But if one exchanges the positions of
residues 15-21 and 36-42, one gets an essentially different structure in the single
chain system, because the other residues have to be rearranged to accommodate the
exchange. This combinatorial advantage of oligomeric structures is another simplifying
factor that allows simulations of larger over-all system sizes in aggregation studies.
Aggregation studies have been performed for several small peptides with ProFASi, such
as Aβ16-22, Aβ25-35,
and the tau peptide fragment, Ac-PHF6. Such peptides are experimentally known to
form amyloid fibrils. Their small size, diverse compositions, combined with the above fact that
they can make fibrils, make such peptides excellent targets for simulation studies. Such simulations
can provide new insights on the details of the aggregation process. These peptides are fragments
of larger peptides related to the Alzheimer's disease. It is now believed that the actual neurotoxic
species are small aggregates of the larger peptides. Simulations of such systems have also
been done with ProFASi.
Left:
A twisted β-sandwich. Greater order in the arrangement of β-strands
correlates in the simulations with an ability to grow.
Right:
Extremely compact and very stable structures like β-barrels form quite
regularly in the simulations of some systems.
The above figure shows two examples of oligomers formed during a study of the
tau peptide fragment Ac-PHF6 (sequence: Ac-VQIVYK-NH2). Very compact structures
such as the β-barrel shown to the right form spontaneously in the simulations. The
animation below shows the formation of the barrel.
Formation of a β-barrel in the simulations. The chains are placed in a periodic box. At one
point in the movie, the barrel, after forming, seems to break in two. In reality, it is located
at the box boundary at that stage.
Broadly, the picture one obtains from ProFASi simulations of the aggregation of small peptides is that
very small oligomers can contain disorder in terms of β-strand organisation (registry,
parallel vs anti-parallel), and yet be stable. Larger oligomers tend to be more ordered. It is easier to
continue an ordered open β-sheet.
References
The results discussed in this page have been discussed in the following article.
- Formation and Growth of Oligomers: A Monte Carlo Study of an Amyloid Tau Fragment,
Da-Wei Li, Sandipan Mohanty, Anders Irbäck and Shuanghong Huo,
(2008)
PLoS Comput. Biol. 4(12):e1000238
- Structural reorganisation and potential toxicity of oligomeric species formed during
the assembly of amyloid fibrils, M. Cheon, I. Chang, S. Mohanty, L.M. Luheshi,
C.M. Dobson, M. Vendruscolo and G. Favrin,
(2007)
PLoSComput. Biol. 3(9): e173.
- Oligomerization of Amyloid Aβ16-22 peptides using hydrogen bonds and hydrophobicity forces,
Giorgio Favrin, Anders Irbäck and Sandipan Mohanty,
(2004) Biophys. J.
87 3657