Programme

I.9 -- Invited, VCTP-44

Date: Tuesday, 30 July 2019

Time: 16:00 - 16:30

Protein aggregation and neurodegenerative diseases

Mai Suan Li (1,2)

(1) Institute of Physics, Polish Academy of Science, Al. Lotnikow 32/46, 02-668 Warsaw, Poland; (2) Institute for Computational Science and Technology, Ho Chi Minh city, Vietnam

Protein aggregation is associated with a large group of major human diseases, including Alzheimer’s disease, prion disorders, type 2 diabetes etc [1]. Therefore, understanding the key factors that govern this process is of paramount importance. It was well-known that the fibril formation time strongly correlated with the hydrophobicity, charge and population of the fibril- prone state of proteins [2]. In this talk, we show that the aggregation rate depends on the mechanical stability of fibril [3] and the beta-content of the monomer [4]. The higher the beta-content, the faster the fibril elongation, and this dependence can be described by a single exponential function. Our results open up a new way of understanding the self-assembly of bio-molecules at the monomer level, and this has been confirmed by all-atom molecular dynamics simulations of amyloid beta (Aβ) peptides and in vitro experiments. Recent research revealed that soluble complexes of Aβ peptides and copper are efficient catalysts in dioxygen activation and, therefore, are potentially dangerous species triggering an irreversible oxidative pathway in Alzheimer’s disease. We have shown [5] that in the presence of Cu(II) the beta-content of monomer is reduced substantially compared with the wildtype Aβ42 suggesting that, in accord with experiment, metal ions facilitate formation of amorphous aggregates rather than amyloid fibrils with cross-β structures. For the Cu:Aβ stoichiometric ratios of 1:1 Cu delays the Aβ dimerization process as observed in a number of experiments. The mechanism underlying this phenomenon is associated with decreased hydrophobicity of monomer upon Cu-binding.
[1] J. Nasica-Labouze, et al., Amyloid beta-protein and Alzheimer's disease: when computer simulations complement experimental studies , Chemical Reviews 115, 3518-3563 (2015).
[2] M.S. Li, N.T. Co, G. Reddy, C-K Hu and D. Thirumalai, Factors governing fibrillogenesis of polypeptide chains revealed by lattice models, Phys. Rev. Lett. 105, 218101 (2010).
[3] M. Kouza et al, Kinetics and mechanical stability of the fibril state control fibril formation time of polypeptide chains: A computational study, J. Chem. Phys. 148, 215106 (2018).
[4] TTM Thu, NT Co, LA Tu, and MS Li, Aggregation rate of amyloid beta peptide is controlled by beta-content in monomeric state, J Chem Phys. 150, 225101 (2019).
[5] P.D.Q. Huy et al., Impact of Cu(II) binding on structures and dynamics of Aβ42 monomer and dimer: Molecular dynamics study, ACS Chem. Neurosci. 10, 1348 (2016).

Presenter: Mai Suan Li