Small-soluble amyloid oligomers are believed to play a significant role in the pathology of amyloid diseases. Recently, the atomic structure of a toxic oligomer formed by an 11 residue and its tandem repeat was found to have an out-off register antiparallel β-strands in the shape of a β-barrel. In the present article we investigate the effect of mutations in the hydrophobic cores on the structure and dynamic of the β-barrels using all atom multiple molecular dynamics simulations with an explicit solvent. Extending previous experiments with molecular dynamics simulations we systematically test how stability and formation of cylindrin depends on the interplay between hydrophobicity and steric effects of the core residues. We find that strong hydrophobic interactions between geometrically fitting residues keep the strands (both in register and out-off-register interface) in close proximity, which in turn stabilizes the side-chain and main-chain hydrogen bonds, and the salt bridges on the outer surface along the weak out-of-register interface. Our simulations also indicate presence of water molecules in the hydrophobic interior of the cylindrin β-barrel.Proteins 2013. © 2013 Wiley Periodicals, Inc.