Robust rare event simulation for protein folding and disease-related aggregation

描述(由申请人提供)：本提案描述了罕见事件方法的开发和应用，这些方法将打开处理一类生物分子问题的大门，这些问题由于其多途径特性而对现有方法具有挑战性。这些问题包括蛋白质折叠和聚集方面的问题仍然悬而未决，尽管近年来在这些领域取得了巨大进展。其关键思想是严格表征方法的误差行为(特别是在低温极限下)，以得出可用于自适应重新聚焦采样以获得最大效率的标准。我们所寻求的方法的特性如下：(I)它们将能够在多于几个反应坐标下操作，以允许在没有明显的描述符选择的情况下处理问题；(Ii)它们将有效地对通过复杂的过渡网络而不是单一的主导路径进行的反应机制进行采样；(Iii)它们将是完全非平衡的，即它们将产生反应轨迹以及那些轨迹的统计特性，包括速率 以及(Iv)它们提供的结果将不取决于反应坐标的特定选择(尽管收敛速度通常会)或任何马尔可夫假设。所提出的方法将被应用于两个蛋白质折叠问题，这两个问题超出了现有的增强采样方法。第一个系统是Beta3S，这是一种由20个残基组成的设计的三链反平行β-折叠微型蛋白质。我们选择这个系统是因为关于它的折叠和展开的数据来自广泛的物理加权分子动力学模拟，并且几个小组的分析表明它具有明确的自然状态和复杂的动力学，这是更大的蛋白质的特征。第二个系统的特征要差得多，但改进的建模方法可以提供具有重大生物医学意义的信息：我们将绘制α-突触核蛋白单体和寡聚体可访问的状态和转变图。α-突触核蛋白是一种140个残基的内在无序蛋白质，与许多神经退行性疾病有关，包括帕金森氏症和路易体痴呆。

DESCRIPTION (provided by applicant): This proposal describes the development and application of rare event methods that will open the door to treating classes of biomolecular problems that are challenging for existing methods owing to their multipathway character. These include problems in protein folding and aggregation that remain outstanding, despite enormous progress in those areas in recent years. The key idea is to rigorously characterize the error behavior of the methods (in particular in the low temperature limit) to derive criteria tat can be used to adaptively refocus sampling for maximal efficiency. The properties of the methods that we seek are as follows: (i) they will be capable of operating with more than a few reaction coordinates to allow treating problems without obvious choices of descriptors, (ii) they will efficiently sample reaction mechanisms that proceed via a complex network of transitions rather than a single dominant pathway, (iii) they will be fully non-equilibrium, i.e., they will generate reactive trajectories and the statistical properties of those trajectories including rates and other dynamical quantities such as time correlation functions, and (iv) the results that they provide will not depend on the particular choice of reaction coordinates (though the convergence rate typically will) or on any Markov assumptions. The proposed methods will be applied to two protein folding problems that are beyond present enhanced sampling methods. The first system is beta3s, a 20-residue designed three-stranded antiparallel beta-sheet miniprotein. We choose this system because data on its folding and unfolding exists from extensive physically weighted molecular dynamics simulations, and analyses by several groups show that it has a well-defined native state and complex dynamics that are characteristic of much larger proteins. The second system is much less well characterized, but improved means for modeling it can provide information of major biomedical significance: we will map the states and transitions accessible to monomers and oligomers of alpha-synuclein, a 140-residue intrinsically disordered protein that is linked to a number of neurodegenerative diseases, including Parkinson's Disease and Dementia with Lewy Bodies.