Soft Matter Science - Molecular Neuroscience

Molecular Neuroscience

We are developing multiscale modeling methods, algorithms and software for molecular neuroscience, in particular, the misfolding and aggregation of key proteins related to various neurodegenerative diseases, such as Huntington's Disease (HD), Alzheimer's Disease (AD), and Parkinson's Disease (PD). The following lists a few representative projects on this important and emerging field.

1. Potential Nanomedicine for AD

The rapid increase of Alzheimer’s disease (AD) concurrent with the aging population worldwide has posed a significant challenge to today’s health care systems. Current therapies for AD, such as small-molecule-based inhibitors, provide a moderate symptomatic reduction or delay at various stages of the disease, but do not arrest the disease progression. As such, novel approaches, including nanomaterial-based nanodrugs or nanotherapies, are in urgent need. Inspired by our recent work on graphene antibacterial activity (Zhou and coworkers, Nature Nanotech 8, 894-601, 2013), where graphene nanosheets can penetrate into cell membranes and also extract large amounts of phospholipids directly from the lipid bilayer, we wonder whether graphene nanosheets could also dissociate and break down the preformed mature amyloid aggregates associated with AD.

In this study, we show, both experimentally and theoretically, that pristine graphene and graphene-oxide nanosheets can not only inhibit the Aβ peptide monomer fibrillation, but also break down mature amyloid fibrils. This provides great promise in reducing the progress of peptide aggregation, a critical step in the AD pathogenesis. Our molecular dynamics simulations first reveal that graphene nanosheets can both penetrate into and extract large amounts of peptides from the preformed amyloid fibrils, due to the exceptionally strong dispersion interactions between graphene and peptides. These interactions are further enhanced by strong π-π stacking between the aromatic residues of the Aβ peptide and graphene once extracted. Atomic force microscopy images then confirm these predictions by showing that mature amyloid fibrils can be cut into pieces by graphene oxides. Thioflavin fluorescence assays further illustrate the detailed dynamic processes of graphene-induced inhibition and dissociation starting from both monomer peptides and mature amyloid fibrils. These findings provide new insights to the underlying molecular mechanism of this important graphene-amyloid interaction, and will promote the development of novel nanotherapies for Alzheimer’s and other related protein conformational diseases.

2. Modeling Huntingtin Protein for HD

Huntington’s disease (HD) is caused by the mutational extension of nucleotide CAG repeats, which encode an elongated polyglutamine (polyQ), within the first exon of the Huntingtin (Htt) gene [1]. In adult onset HD, pathogenic threshold Q-length is between 36 and 40, with individuals with fewer repeats showing no disease activity. The strong correlation between increased CAG repeats in Htt and the development of HD was also confirmed by mouse models as well as in vitro experiments. Notwithstanding the well-established negative correlation between the length of polyQ and the onset age of HD, the mechanism by which expanded polyQ tracts cause dysfunction of neurons and lead to cell death is still unclear. Thus, a systematic study on how the polyQ-length affects the Htt protein structure, dynamics and its interaction with others is critical. We are currently using extensive all-atom molecular dynamics (MD) simulations of the full exon-1 of Htt with various polyQ-lengths to investigate the structural and polymeric properties of wtHtt (Q22) and mtHtt (other Q-lengths) that may trigger the formation of HD-related protein aggregates.

Related Publications:

  • Zaixing Yang, Cuicui Ge, Jiajia Liu, Yu Chong, Zonglin Gu, Camilo A. Jimenez-Cruz, Zhifang Chai, R. H. Zhou,
    Destruction of amyloid fibrils by graphene through penetration and extraction of peptides,
    Nanoscale 7, 18725-18737, 2015
  • B. Dai, S. G. Kang, T. Huynh, H. Z. Lei, M. Castelli, J. Hu, Y. Zhang and R. H. Zhou,
    Salts Drive Controllable Multi-Layered Upright Assembly of Amyloid-like Peptides at Mica/Water Interface,
    Proc. Natl. Acad. Sci. 110, 8543-8548, 2013
  • S. G. Kang, T. Huynh, Z. Xia, Y. Zhang, H. P. Fang, G. H. Wei and R. H. Zhou,
    Hydrophobic Interaction Drives Surface-Assisted Epitaxial Assembly of Amyloid-like Peptides,
    J. Am. Chem. Soc. 135, 3150-3157, 2013







  • Otitoaleke G. Akinola
  • David R. Bell
  • Matteo Castelli
  • Camilo Jimenez
  • Yuxing Peng
  • Michael Pitman
  • Raul Araya Secchi
  • Frank Suits
  • Jacinta Wubben
  • Zhen Xia
  • Payel Das