title: Preformed template fluctuations promote fibril formation: insights from lattice and all-atom models.
abstract: Fibril formation resulting from protein misfolding and aggregation is a hallmark of several neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Despite the fact that the fibril formation process is very slow and thus poses a significant challenge for theoretical and experimental studies, a number of alternative pictures of molecular mechanisms of amyloid fibril formation have been recently proposed. What seems to be common for the majority of the proposed models is that fibril elongation involves the formation of pre-nucleus seeds prior to the creation of a critical nucleus. Once the size of the pre-nucleus seed reaches the critical nucleus size, its thermal fluctuations are expected to be small and the resulting nucleus provides a template for sequential (one-by-one) accommodation of added monomers. The effect of template fluctuations on fibril formation rates has not been explored either experimentally or theoretically so far. In this paper, we make the first attempt at solving this problem by two sets of simulations. To mimic small template fluctuations, in one set, monomers of the preformed template are kept fixed, while in the other set they are allowed to fluctuate. The kinetics of addition of a new peptide onto the template is explored using all-atom simulations with explicit water and the GROMOS96 43a1 force field and simple lattice models. Our result demonstrates that preformed template fluctuations can modulate protein aggregation rates and pathways. The association of a nascent monomer with the template obeys the kinetics partitioning mechanism where the intermediate state occurs in a fraction of routes to the protofibril. It was shown that template immobility greatly increases the time of incorporating a new peptide into the preformed template compared to the fluctuating template case. This observation has also been confirmed by simulation using lattice models and may be invoked to understand the role of template fluctuations in slowing down fibril elongation in vivo.
authors: Faculty of Chemistry, University of Warsaw, ul. Pasteura 1, 02-093 Warszaw, Poland.
authors: Maksim
authors: M
authors: Kouza
authors: Department of Physics, Institute of Technology, National University of HCM City, 268 Ly Thuong Kiet Street, District 10, Ho Chi Minh City, Viet Nam.
authors: Nguyen Truong
authors: NT
authors: Co
authors: Laboratoire de Biochimie Theorique, UPR 9080 CNRS, IBPC, Universite Paris 7, 13 rue Pierre et Marie Curie, 75005 Paris, France.
authors: Phuong H
authors: PH
authors: Nguyen
authors: Faculty of Chemistry, University of Warsaw, ul. Pasteura 1, 02-093 Warszaw, Poland.
authors: Andrzej
authors: A
authors: Kolinski
authors: Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668 Warsaw, Poland.
authors: Mai Suan
authors: MS
authors: Li
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D019277:Entropy; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry*; D055503:Protein Multimerization; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C417223:amyloid beta-protein (16-22)