Source:http://linkedlifedata.com/resource/pubmed/id/15644211
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
5
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| pubmed:dateCreated |
2005-1-12
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| pubmed:abstractText |
Characterization of the early stages of peptide aggregation is of fundamental importance in elucidating the mechanism of the formation of deposits associated with amyloid disease. The initial step in the pathway of aggregation of the Abeta-protein, whose monomeric NMR structure is known, was studied through the simulation of the structure and stability of the peptide dimer in aqueous solution. A protocol based on shape complementarity was used to generate an assortment of possible dimer structures. The structures generated based on shape complementarity were evaluated using rapidly computed estimates of the desolvation and electrostatic interaction energies to identify a putative stable dimer structure. The potential of mean force associated with the dimerization of the peptides in aqueous solution was computed for both the hydrophobic and the electrostatic driven forces using umbrella sampling and classical molecular dynamics simulation at constant temperature and pressure with explicit solvent and periodic boundary conditions. The comparison of the two free energy profiles suggests that the structure of the peptide dimer is determined by the favorable desolvation of the hydrophobic residues at the interface. Molecular dynamics trajectories originating from two putative dimer structures indicate that the peptide dimer is stabilized primarily through hydrophobic interactions, while the conformations of the peptide monomers undergo substantial structural reorganization in the dimerization process. The finding that the phi-dimer may constitute the ensemble of stable Abeta(10-35) dimer has important implications for fibril formation. In particular, the expulsion of water molecules at the interface might be a key event, just as in the oligomerization of Abeta(16-22) fragments. We conjecture that events prior to the nucleation process themselves might involve crossing free energy barriers which depend on the peptide-peptide and peptide-water interactions. Consistent with existing experimental studies, the peptides within the ensemble of aggregated states show no signs of formation of secondary structure.
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| pubmed:grant | |
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Feb
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| pubmed:issn |
0022-2836
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
4
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| pubmed:volume |
345
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| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
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| pubmed:pagination |
1141-56
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| pubmed:dateRevised |
2010-11-18
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| pubmed:meshHeading |
pubmed-meshheading:15644211-Amyloid beta-Peptides,
pubmed-meshheading:15644211-Computer Simulation,
pubmed-meshheading:15644211-Dimerization,
pubmed-meshheading:15644211-Models, Molecular,
pubmed-meshheading:15644211-Peptide Fragments,
pubmed-meshheading:15644211-Protein Structure, Quaternary,
pubmed-meshheading:15644211-Protein Structure, Secondary,
pubmed-meshheading:15644211-Static Electricity,
pubmed-meshheading:15644211-Time Factors
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| pubmed:year |
2005
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| pubmed:articleTitle |
Probing the initial stage of aggregation of the Abeta(10-35)-protein: assessing the propensity for peptide dimerization.
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| pubmed:affiliation |
Department of Chemistry, Boston University, Boston, MA 02215, USA.
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| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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