What factor drives the fibrillogenic association of β‐sheets?

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Abstract
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.