期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 324, 期 4, 页码 851-857出版社
ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD
DOI: 10.1016/S0022-2836(02)01112-9
关键词
amyloidogenesis; discrete molecular dynamics; dimerization; amyloid fibril; aggregation
资金
- NIGMS NIH HHS [GM20251, GM52126] Funding Source: Medline
We use molecular dynamics simulation to study the aggregation of Src SH3 domain proteins. For the case of two proteins, we observe two possible aggregation conformations: the closed form dimer and the open aggregation state. The closed dimer is formed by domain swapping-the two proteins exchange their RT-loops. All the hydrophobic residues are buried inside the dimer so proteins cannot further aggregate into elongated amyloid fibrils. We find that the open structure-stabilized by backbone hydrogen bond interactions-packs the RT-loops together by swapping the two strands of the RT-loop. The packed RT-loops form a beta-sheet structure and expose the backbone to promote further aggregation. We also simulate more than two proteins, and find that the aggregate adopts a fibrillar double beta-sheet structure, which is formed by packing the RT-loops from different proteins. Our simulations are consistent with a possible generic amyloidogenesis scenario. (C) 2002 Elsevier Science Ltd. All rights reserved.
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