Long-range Regulation of Partially Folded Amyloidogenic Peptides

被引:11
|
作者
Bhattacharya, Shayon [1 ]
Xu, Liang [1 ]
Thompson, Damien [1 ]
机构
[1] Univ Limerick, Bernal Inst, Dept Phys, Limerick V94 T9PX, Ireland
基金
爱尔兰科学基金会;
关键词
INTRINSICALLY DISORDERED PROTEINS; PARTICLE MESH EWALD; MOLECULAR-DYNAMICS; ALPHA-SYNUCLEIN; BETA-PEPTIDE; FORCE-FIELD; HYDROPHOBIC INTERACTIONS; CORRELATED DYNAMICS; REPLICA EXCHANGE; ALZHEIMERS;
D O I
10.1038/s41598-020-64303-x
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Neurodegeneration involves abnormal aggregation of intrinsically disordered amyloidogenic peptides (IDPs), usually mediated by hydrophobic protein-protein interactions. There is mounting evidence that formation of alpha -helical intermediates is an early event during self-assembly of amyloid-beta 42 (A beta 42) and alpha -synuclein (alpha S) IDPs in Alzheimer's and Parkinson's disease pathogenesis, respectively. However, the driving force behind on-pathway molecular assembly of partially folded helical monomers into helical oligomers assembly remains unknown. Here, we employ extensive molecular dynamics simulations to sample the helical conformational sub-spaces of monomeric peptides of both A beta 42 and alpha S. Our computed free energies, population shifts, and dynamic cross-correlation network analyses reveal a common feature of long-range intra-peptide modulation of partial helical folds of the amyloidogenic central hydrophobic domains via concerted coupling with their charged terminal tails (N-terminus of A beta 42 and C-terminus of alpha S). The absence of such inter-domain fluctuations in both fully helical and completely unfolded (disordered) states suggests that long-range coupling regulates the dynamicity of partially folded helices, in both A beta 42 and alpha S peptides. The inter-domain coupling suggests a form of intra-molecular allosteric regulation of the aggregation trigger in partially folded helical monomers. This approach could be applied to study the broad range of amyloidogenic peptides, which could provide a new path to curbing pathogenic aggregation of partially folded conformers into oligomers, by inhibition of sites far from the hydrophobic core.
引用
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页数:17
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