New Multiscale Tools for Protein Physics: Thermal Protein Dynamics in Signalling and Allostery.

蛋白质是大自然的分子机器。由24个小分子组成的字母表连接成长链，以折叠的形式，它们构成了所有生物组织和细胞的结构，支架，信号通路，运输系统，发动机和货物运输机。由于它们精致的进化和精确的结构已经通过X射线散射阐明，重点是了解这些结构如何导致功能（例如在特殊的口袋和裂缝中与特定的小分子结合）。然而，最近人们已经清楚，蛋白质的恒定动力学激发，有限温度环境的自然结果，也在功能中发挥着至关重要的作用。来自仔细的热分析和磁共振测量的数据表明，蛋白质的结合事件如何显著改变其内部无休止摆动的性质。此外，申请人最近的工作表明，蛋白质的数学和物理模型如何分析这些运动，并确定它们的变化如何用于在蛋白质网络中产生重要信号。这些控制着细胞功能的各个方面，因此理解它们在生物学中非常重要。该项目的目标是建立在粗粒度蛋白质建模的初始基础上，并以预测的方式将整个蛋白质分子的全局模型与其原子结构联系起来。物理学家和化学家将与生物学家合作，在一系列模型蛋白质系统上验证这些新工具。通过对蛋白质进行微小的改变（突变），模型的预测可以通过实验进行测试。一个特别的目标是使用该技术来设计一种具有全新的变构特性的新蛋白质，这些特性已经在粗粒模型的基础上被工程化到蛋白质中。这将展示生物技术科学商业化的潜在途径。在项目结束时，全球蛋白质动态的系统分析工具将提供给学术界和工业界。

Proteins are natures molecular machines. Built out of an alphabet of only 24 small molecules joined into long chains, in folded-form they constitute the structures, scaffolds, signalling pathways, transport systems, motors and cargo transporters of the tissues and cells of all living things. Since their exquisitely evolved and precise structures have been elucidated through X-ray scattering, the emphasis has been on understanding how these structures lead to function (such as binding to specific small molecules at special pockets and clefts). More recently however, it has become clear that the constant dynamical excitations of proteins, a natural consequence of a finite-temperature environment, also play a vital role in function. Data from careful thermal analysis, and also from magnetic resonance measurements, have shown how binding events at proteins can change the nature of their internal ceaseless wobbling considerably. Furthermore, recent work by the applicants has shown how mathematical and physical models of proteins can analyse these motions and identify how their changes are used to generate vital signals within protein networks. These control all aspects of cell function, so understanding them is very important in biology.The goal of this project is to build on the initial foundations of coarse-grained protein modelling and link the global models of entire protein molecules to their atomistic structure in a predictive way. The physicists and chemists will work with biologists in validating these new tools on a series of model protein systems. By making tiny changes in the proteins ( mutations ), predictions of the models can be tested by experiments. A particular goal is to use the technique to design a new protein with entirely new allostetric properties that have been engineered into the protein on the basis of the course-grained model. This will demonstrate a potential route to commercialisation of the science in biotechnology.At the end of the project, a systematic analytical tool for global protein dynamics will be available to the community, both academic and industrial.