Transmembrane β-Barrel Models of α-Synuclein Oligomers

The aggregation of alpha-synuclein is implicated in a number of neurodegenerative diseases, such as Parkinson's and Multiple System Atrophy, but the role of these aggregates in disease development is not clear. One possible mechanism of cytotoxicity is the disturbance or permeabilization of cell membranes by certain types of oligomers. However, no high-resolution structure of such membrane-embedded complexes has ever been determined. Here we construct and evaluate putative transmembrane beta-barrels formed by this protein. Examination of the alpha-synuclein sequence reveals two regions that could form membrane-embedded beta-hairpins: 64-92 (the NAC), and 35-56, which harbors many familial Parkinson's mutations. The stability of beta-barrels formed by these hairpins is examined first in implicit membrane pores and then by multimicrosecond all-atom simulations. We find that a NAC region barrel remains stably inserted and hydrated for at least 10 mu s. A 35-56 barrel remains stably inserted in the membrane but dehydrates and collapses if all His50 are neutral or if His50 is replaced by Q. If half of the His50 are doubly protonated, the barrel takes an oval shape but remains hydrated for at least 10 mu s. Possible implications of these findings for alpha-synuclein pathology are discussed.