Kouza Maksim, Co Nguyen Truong, Nguyen Phuong H, Kolinski Andrzej, Li Mai Suan
Faculty of Chemistry, University of Warsaw, ul. Pasteura 1, 02-093 Warszaw, Poland.
Department of Physics, Institute of Technology, National University of HCM City, 268 Ly Thuong Kiet Street, District 10, Ho Chi Minh City, Viet Nam.
J Chem Phys. 2015 Apr 14;142(14):145104. doi: 10.1063/1.4917073.
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.
由蛋白质错误折叠和聚集导致的原纤维形成是阿尔茨海默病和帕金森病等几种神经退行性疾病的标志。尽管原纤维形成过程非常缓慢，给理论和实验研究带来了重大挑战，但最近已经提出了许多关于淀粉样原纤维形成分子机制的不同观点。大多数提出的模型似乎共同之处在于，原纤维伸长涉及在形成临界核之前形成前核种子。一旦前核种子的大小达到临界核大小，预计其热涨落会很小，由此产生的核为添加单体的顺序（逐个）容纳提供了模板。到目前为止，尚未从实验或理论上探索模板涨落对原纤维形成速率的影响。在本文中，我们首次尝试通过两组模拟来解决这个问题。为了模拟小的模板涨落，在一组模拟中，预先形成的模板的单体保持固定，而在另一组模拟中，允许它们涨落。使用包含显式水和GROMOS96 43a1力场的全原子模拟以及简单晶格模型，探索了新肽添加到模板上的动力学。我们的结果表明，预先形成的模板涨落可以调节蛋白质聚集速率和途径。新生单体与模板的结合遵循动力学分配机制，其中中间态出现在通向原纤维的部分路径中。结果表明，与涨落的模板情况相比，模板固定大大增加了将新肽纳入预先形成的模板的时间。使用晶格模型的模拟也证实了这一观察结果，并且可以用来理解模板涨落在体内减缓原纤维伸长中的作用。
