What factor drives the fibrillogenic association of β-sheets?

The identification of the driving factor for fibril formation is paramount to understand the molecular basis of amyloidogenic disease. Recently, an atomic-detail structure of a fibrillogenic aggregate was reported and revealed a tight packing of β-sheets. However, there is not a single pair-wise interaction of significance between the β-sheets, no hydrogen bond and no hydrophobic interaction. Instead, there is extensive burial of polar groups at the interface. These observations lead to the question: What factor drives the association of β-sheets? This issue is addressed by combining all-atom molecular dynamics with an implicit-solvent analysis. The driving force for the association arises from the mechanical equivalent of the dehydration propensity of pre-formed intra-sheet hydrogen bonds and dipole–dipole interactions.