Journal
BIOCHEMISTRY
Volume 50, Issue 35, Pages 7612-7628Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi200732x
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Funding
- National Institutes of Health (NIH) [T32 GM08295]
- NERSC
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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.
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