dorsal/arxiv
View SchemaRole of electrostatic interactions in amyloid beta-protein (Abeta) oligomer formation: A discrete molecular dynamics study
| Authors | Sijung Yun, Brigita Urbanc, Luis Cruz, Gal Bitan, David B. Teplow, H. Eugene Stanley |
|---|---|
| Categories | |
| ArXiv ID | q-bio/0701037 |
| URL | https://arxiv.org/abs/q-bio/0701037 |
| DOI | 10.1529/biophysj.106.097766 |
Abstract
Pathological folding and oligomer formation of the amyloid beta-protein (Abeta) are widely perceived as central to Alzheimer's disease (AD). Experimental approaches to study Abeta self-assembly are problematic, because most relevant aggregates are quasi-stable and inhomogeneous. We apply a discrete molecular dynamics (DMD) approach combined with a four-bead protein model to study oligomer formation of the amyloid beta-protein (Abeta). We address the differences between the two most common Abeta alloforms, Abeta40 and Abeta42, which oligomerize differently in vitro. We study how the presence of electrostatic interactions (EIs) between pairs of charged amino acids affects Abeta40 and Abeta42 oligomer formation. Our results indicate that EIs promote formation of larger oligomers in both Abeta40 and Abeta42. The Abeta40 size distribution remains unimodal, whereas the Abeta42 distribution is trimodal, as observed experimentally. Abeta42 folded structure is characterized by a turn in the C-terminus that is not present in Abeta40. We show that the same C-terminal region is also responsible for the strongest intermolecular contacts in Abeta42 pentamers and larger oligomers. Our results suggest that this C-terminal region plays a key role in the formation of Abeta42 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 Abeta42 oligomers may be able to prevent oligomer formation or structurally modify the assemblies to reduce their toxicity.
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"abstract": "Pathological folding and oligomer formation of the amyloid beta-protein\n(Abeta) are widely perceived as central to Alzheimer\u0027s disease (AD).\nExperimental approaches to study Abeta self-assembly are problematic, because\nmost relevant aggregates are quasi-stable and inhomogeneous. We apply a\ndiscrete molecular dynamics (DMD) approach combined with a four-bead protein\nmodel to study oligomer formation of the amyloid beta-protein (Abeta). We\naddress the differences between the two most common Abeta alloforms, Abeta40\nand Abeta42, which oligomerize differently in vitro. We study how the presence\nof electrostatic interactions (EIs) between pairs of charged amino acids\naffects Abeta40 and Abeta42 oligomer formation. Our results indicate that EIs\npromote formation of larger oligomers in both Abeta40 and Abeta42. The Abeta40\nsize distribution remains unimodal, whereas the Abeta42 distribution is\ntrimodal, as observed experimentally. Abeta42 folded structure is characterized\nby a turn in the C-terminus that is not present in Abeta40. We show that the\nsame C-terminal region is also responsible for the strongest intermolecular\ncontacts in Abeta42 pentamers and larger oligomers. Our results suggest that\nthis C-terminal region plays a key role in the formation of Abeta42 oligomers\nand the relative importance of this region increases in the presence of EIs.\nThese results suggest that inhibitors targeting the C-terminal region of\nAbeta42 oligomers may be able to prevent oligomer formation or structurally\nmodify the assemblies to reduce their toxicity.",
"arxiv_id": "q-bio/0701037",
"authors": [
"Sijung Yun",
"Brigita Urbanc",
"Luis Cruz",
"Gal Bitan",
"David B. Teplow",
"H. Eugene Stanley"
],
"categories": [
"q-bio.BM"
],
"doi": "10.1529/biophysj.106.097766",
"title": "Role of electrostatic interactions in amyloid beta-protein (Abeta) oligomer formation: A discrete molecular dynamics study",
"url": "https://arxiv.org/abs/q-bio/0701037"
},
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