Role of electrostatic interactions in amyloid beta-protein (A beta) oligomer formation: a discrete molecular dynamics study.

Role of electrostatic interactions in amyloid beta-protein (A beta) oligomer formation: a discrete molecular dynamics study. Research Abstract Details 

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Role of electrostatic interactions in amyloid beta-protein (A beta) oligomer formation: a discrete molecular dynamics study. Abstract Text:

Sijung Yun,B Urbanc,L Cruz,G Bitan,D B Teplow,H E Stanley,

Pathological folding and oligomer formation of the amyloid beta-protein (A beta) are widely perceived as central to Alzheimer's disease. Experimental approaches to study A beta self-assembly provide limited information because most relevant aggregates are quasi-stable and inhomogeneous. We apply a discrete molecular dynamics approach combined with a four-bead protein model to study oligomer formation of A beta. We address the differences between the two most common A beta alloforms, A beta 40 and A beta 42, which oligomerize differently in vitro. Our previous study showed that, despite simplifications, our discrete molecular dynamics approach accounts for the experimentally observed differences between A beta 40 and A beta 42 and yields structural predictions amenable to in vitro testing. Here we study how the presence of electrostatic interactions (EIs) between pairs of charged amino acids affects A beta 40 and A beta 42 oligomer formation. Our results indicate that EIs promote formation of larger oligomers in both A beta 40 and A beta 42. Both A beta 40 and A beta 42 display a peak at trimers/tetramers, but A beta 42 displays additional peaks at nonamers and tetradecamers. EIs thus shift the oligomer size distributions to larger oligomers. Nonetheless, the A beta 40 size distribution remains unimodal, whereas the A beta 42 distribution is trimodal, as observed experimentally. We show that structural differences between A beta 40 and A beta 42 that already appear in the monomer folding, are not affected by EIs. A beta 42 folded structure is characterized by a turn in the C-terminus that is not present in A beta 40. We show that the same C-terminal region is also responsible for the strongest intermolecular contacts in A beta 42 pentamers and larger oligomers. Our results suggest that this C-terminal region plays a key role in the formation of A beta 42 oligomers and the relative importance of this region increases in the presence of EIs. These results suggest that inhibitors targeting the C-terminal region of A beta 42 oligomers may be able to prevent oligomer formation or structurally modify the assemblies to reduce their toxicity.

Role of electrostatic interactions in amyloid beta-protein (A beta) oligomer formation: a discrete molecular dynamics study. Publishing Authors By Initials

S Yun,B Urbanc,L Cruz,G Bitan,DB Teplow,HE Stanley,

For similar natural sciences: science: models, theoretical: models, chemical research abstracts see: natural sciences: science: models, theoretical: models, chemical research

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Role of electrostatic interactions in amyloid beta-protein (A beta) oligomer formation: a discrete molecular dynamics study. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Biophysical journal

VOLUME: 92

Page Numbers: 4064-77

Journal Abbreviation: Biophys. J.

ISSN: 0006-3495

DAY: 16

MONTH: 02

YEAR: 2007

Role of electrostatic interactions in amyloid beta-protein (A beta) oligomer formation: a discrete molecular dynamics study. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 370626

Role of electrostatic interactions in amyloid beta-protein (A beta) oligomer formation: a discrete molecular dynamics study. Keywords Mesh Terms:

KEYWORDS: Models, Chemical

MESH TERMS: metabolism

Chemical & Substance for Abstract: Role of electrostatic interactions in amyloid beta-protein (A beta) oligomer formation: a discrete molecular dynamics study. Information

Substance Name: Amyloid beta-Protein

Registry Number: 0

Grant and Affiliation Information for Role of electrostatic interactions in amyloid beta-protein (A beta) oligomer formation: a discrete molecular dynamics study.

AFFILIATION: Center for Polymer Studies, Department of Physics, Boston University, Boston, Massachusetts, USA.

Country: United States

AGENCY: United States NINDS

GRANT: NS44147

ACRONYM: NS

MEDLINETA: Biophys J

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