The Energy Landscapes of Protein Folding and Function: Connecting Theory and Experiments

许多细胞功能依赖于蛋白质之间以及蛋白质和核酸之间的相互作用。这个项目的总体目标是由生物科学局分子和细胞生物科学部的分子生物物理学和数学和物理科学局物理部的生物物理计划共同支持，旨在破译生物分子自组装过程的基本原理，最终目的是从物理的角度理解细胞网络组织的原理。能量景观理论和漏斗概念促进了人们对单一蛋白质链强健地自组装成其独特的自然结构的理解。对于小蛋白质，最小能量受挫的简化模型将被推广到研究局部几何细节、非自然相互作用和去溶解对折叠机制的影响。更大的蛋白质，具有更复杂的能量格局，将被研究以表征其折叠机制、动力学、途径和中间产物。然而，仅仅折叠是不够的，以获得功能的全部画面。功能需要改变结构和特定的识别，以形成复合体，并使细胞内的无线通信成为可能。这项研究将通过以下两个方面来解决：(1)使用包含蛋白质的多个稳定构象的广义简化模型来探索与功能相关的构象转变。与宏观机器不同，蛋白质是一种生物机器，可以在运行过程中局部断裂，然后重新组装。将开发全球结构转换的模型，如变构和分子通讯。它们涉及大规模运动和可能的部分展开。(2)探索在细胞环境中支配蛋白质-蛋白质相互作用的蛋白质结合的物理和化学原理。这些原理必须在研究特异性、亲和力和交叉反应性之前制定出来。了解蛋白质的这些全局/功能运动不仅可以提供对生物现象的理解，而且通过学习这些纳米级分子机器的功能和设计原理，它将在纳米科学中产生重大影响。使用模仿这些生物分子机器的设计原理将使我们能够开发一种全新的材料家族，这些材料在纳米尺度上发挥作用，具有传感和催化等应用。NSF的支持对于培养高度交叉的分子生物物理学领域的学生和博士后研究员至关重要。除了理论培训外，对实验的深入理解也是必不可少的。五名前博士后研究员和两名研究生现在是主要大学的教授。在他的研究中，PI一直有很好的女性代表和代表不足群体的成员。

Many cellular functions rely on interactions among proteins and between proteins and nucleic acids. The overall goal of this project, jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Biological Physics Program in the Division of Physics in the Mathematical and Physical Sciences Directorate, is to decipher the first principles of self-assembly processes of biomolecules with the ultimate aim to understand the principles of cellular network organization from a physical viewpoint. Energy landscape theory and the funnel concept have advanced the understanding of the robust self-assembly of a single protein chain into its uniquely native structure. For small proteins, the reduced models that are minimally energetically frustrated will be generalized to study the effects of local geometrical details, non-native interactions, and desolvation on folding mechanisms. Larger proteins, which have much more complex energy landscapes, will be studied to characterize their folding mechanisms, kinetics, pathways, and intermediates. Folding alone, however, is not sufficient for a full picture of function. Function requires change of structure and specific recognition to form complexes and to enable the wireless communication in the cell. This research will address these two aspects by: (1) Exploring the conformational transitions associated with function using generalized reduced models that incorporate the multiple stable conformations of the protein. Unlike macroscopic machines, proteins are biological machines that can locally break and then reassemble during function. Models for global structural transformations, such as allostery and molecular communication, will be developed. They involve large-scale motions and possible partial unfolding. (2) Exploring the physical and chemical principles of protein binding that govern the protein-protein interactions in the context of the cell. Such principles have to be formulated before one turns to study specificity, affinity, and cross-reactivity. Understanding these global/functional motions of proteins will not only provide an understanding of the biological phenomena but, by learning the function and designing principles of these nanoscale molecular machines, it will lead to a major impact in nanoscience. Using designing principles that mimic these biomolecular machines will allow us to develop an entirely new family of materials, which function at the nanoscale, with applications such as sensing and catalysis.The NSF support has been vital for training students and postdoctoral fellows in the highly interdisciplinary field of molecular biophysics. Besides theoretical training, a strong understanding of the experiments is essential. Five former postdoctoral fellows and two graduate students are now professors at major universities. The PI has always had a good representation of women and members from underrepresented groups in his research.