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与核酸之间的相互作用。本项目由生物科学部分子与细胞生物科学部分子生物物理学和数理化部物理部生物物理项目共同支持，其总体目标是破译生物分子自组装过程的基本原理，并最终从物理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对单个蛋白质链的强大自组装到其独特的天然结构的理解。对于小蛋白质，将最小能量受挫的简化模型推广到研究局部几何细节、非原生相互作用和溶解对折叠机制的影响。更大的蛋白质，具有更复杂的能量景观，将研究表征其折叠机制，动力学，途径和中间体。然而，仅靠折叠是不足以全面了解功能的。功能需要改变结构和特异性识别来形成复合物并使细胞内的无线通信成为可能。本研究将通过以下两个方面来解决这两个问题：(1)利用包含蛋白质多种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，蛋白质是生物机器，可以局部断裂，然后在功能过程中重新组装。将开发全局结构转换的模型，例如变构和分子通信。它们包括大规模的运动和可能的局部展开。(2)探索在细胞背景下控制蛋白质-蛋白质相互作用的蛋白质结合的物理和化学原理。在研究特异性、亲和性和交叉反应性之前，必须制定这些原则。了解这些蛋白质的全局/功能运动不仅有助于理解生物现象，而且通过学习这些纳米级分子机器的功能和设计原理，将对纳米科学产生重大影响。利用模仿这些生物分子机器的设计原理，我们将开发出一种全新的材料家族，它在纳米尺度上起作用，应用于传感和催化等领域。美国国家科学基金会的支持对于培养分子生物物理学高度跨学科领域的学生和博士后至关重要。除了理论训练，对实验的深刻理解也是必不可少的。5名前博士后和2名研究生现在是主要大学的教授。在他的研究中，PI一直很好地代表了女性和来自代表性不足群体的成员。

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.