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
收藏
页数:17
相关论文
共 50 条
  • [22] Polycomb Group Proteins and Long-Range Gene Regulation
    Mateos-Langerak, Julio
    Cavalli, Giacomo
    LONG-RANGE CONTROL OF GENE EXPRESSION, 2008, 61 : 45 - 66
  • [23] Cooperativity in long-range gene regulation by the λ CI repressor
    Dodd, IB
    Shearwin, KE
    Perkins, AJ
    Burr, T
    Hochschild, A
    Egan, JB
    GENES & DEVELOPMENT, 2004, 18 (03) : 344 - 354
  • [24] Long-range gene regulation in the context of chromatin domains
    Dekker, Job
    FASEB JOURNAL, 2016, 30
  • [25] Long-Range Regulation of Key Sex Determination Genes
    Migale, Roberta
    Neumann, Michelle
    Lovell-Badge, Robin
    SEXUAL DEVELOPMENT, 2021, 15 (5-6) : 360 - 380
  • [26] LONG-RANGE ELECTRON-TRANSFER BETWEEN TYROSINE AND TRYPTOPHAN IN PEPTIDES
    FARAGGI, M
    DEFELIPPIS, MR
    KLAPPER, MH
    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1989, 111 (14) : 5141 - 5145
  • [27] Long-range and very long-range charge transport in DNA
    Bixon, M
    Jortner, J
    CHEMICAL PHYSICS, 2002, 281 (2-3) : 393 - 408
  • [28] Distance dependence of long-range electron transfer through helical peptides
    Kai, Minako
    Takeda, Kazuki
    Morita, Tomoyuki
    Kimura, Shunsaku
    JOURNAL OF PEPTIDE SCIENCE, 2008, 14 (02) : 192 - 202
  • [29] Long-range gene regulation in hormone-dependent cancer
    Theophilus T. Tettey
    Lorenzo Rinaldi
    Gordon L. Hager
    Nature Reviews Cancer, 2023, 23 : 657 - 672
  • [30] Genome organization and long-range regulation of gene expression by enhancers
    Smallwood, Andrea
    Ren, Bing
    CURRENT OPINION IN CELL BIOLOGY, 2013, 25 (03) : 387 - 394