Homogeneous and Heterogeneous Tertiary Structure Ensembles of Amyloid-β Peptides

The interplay of modern molecular simulation and high-quality nuclear magnetic resonance (NMR) experiments has reached a fruitful stage for quantitative characterization of structural ensembles of disordered peptides., Amyloid-beta 1-42 (A beta 42), the primary peptide associated with Alzheimer's disease, and fragments such as A beta 21-30 are both classified as intrinsically disordered peptides (IDPs). We use a variety of NMR observables to validate de novo molecular dynamics simulations in explicit water to characterize the tertiary structure ensemble of A beta 42 and A beta 21-30 from the perspective of their classification as IDPs. Unlike the A beta 21-30 fragment that conforms to expectations of an IDP that is primarily extended, we find that A beta 42 samples conformations reflecting all possible secondary structure categories and spans the range of IDP classifications from collapsed structured states to highly extended conformations, making it an IDP with a far more heterogeneous tertiary ensemble.