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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.

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.