Collaborative Proposal: CDI-Type I: A multidisciplinary, multiscale approach to discover organizing principles in macromolecular dynamics and functions

理解生物分子系统中的合作过程（如蛋白质动力学、折叠和自组装）对理论和实验都提出了突出的挑战。所涉及的大量自由度和存在的异质性程度，乍一看可能表明缺乏一般原则。正如弗朗西斯·克里克（Francis Crick）在20年前评论大分子动力学时所写的那样，“在物理学家看来是无可救药的复杂过程，可能是大自然发现的最简单的过程”。大分子系统的行为显得极其复杂。生物相关的大分子系统是数十亿年进化的结果，在此过程中，由于功能原因，细节和例外被选择。尽管复杂，集体现象出现在大分子系统中，例如在蛋白质折叠和自组装过程中，这表明存在组织原则，实际上可能利用复杂性来获得简单性。是否有可能理解（即再现、量化和预测）生物分子系统中单个自由度的相互作用如何在广泛的长度和时间尺度上产生组织？经验和理论证据支持这样的观点，即对于大多数大分子过程，只访问了构象空间的一小部分，并且对于中/长时间尺度，非常少量的参数足以描述大型大分子系统的粗略动力学。以前在这个方向上的工作不是自动的，也不是系统的，而且主要是由物理直觉驱动的，很少或根本没有成功的保证。这项工作的目标是开发和应用一种完全不同的方法，将生物学和生物化学方法与物理和数学观点相协调。形成进化用来调节生物分子过程行为的一般“规则”的关键一步在于数学上严格的识别和感兴趣的物理上健全的大分子过程。为此目的而开发的基于多尺度的方法将广泛适用于大型高维数据集的几何分析，跨数据集和此类数据集。

The understanding of cooperative processes in biomolecular systems (such as protein dynamics, folding, and self-assembly) poses outstanding challenges both for theory and experiment. The large number of degrees of freedom involved, and the degree of heterogeneity present, may at a first glance suggest the lack of general principles. As Francis Crick wrote twenty years ago, commenting on macromolecular dynamics, "what seems to physicists a hopelessly complicated process may have been what Nature found simplest". The behavior of a macro-molecular system appears overwhelmingly complicated. Biologically relevant macro-molecular systems are the result of billions of years of evolution, during which details and exceptions have been selected for functional reasons. In spite of the complexity, collective phenomena emerge in macromolecular systems, as for instance in protein folding and self-assembly processes, suggesting the existence of organizing principles that may actually exploit the complexity to obtain simplicity.Is it possible to understand (that is, reproduce, quantify, and predict) how organization emerges from the interactions of the single degrees of freedom in a biomolecular system, over a broad spectrum of length and timescales? Empirical and theoretical evidence supports the idea that for most macromolecular processes only a small portion of the conformational space is visited, and that for medium/long time scales a very small number of parameters are enough to describe the coarse dynamics of a large macromolecular system. Previous work in this direction has not been automatic nor systematic, and has been driven mostly by physical intuition, with little or no guarantee of success.It is the goal of this work to develop and apply a radically different approach, that reconciles biological and biochemical approaches with a physical and mathematical perspective. A key step towards the formulation of the general "rules" that evolution has employed for regulating the behavior of biomolecular processes resides in the mathematically rigorous identification and the physically sound macromolecular process of interest. The methods that will be developed to this end are based on multiscale will be widely applicable to the analysis of the geometry of large high dimensional data sets, across and such data sets.