Single Molecule Studies of Protein Folding

理解生命规律的一个根本障碍是对基因组编码蛋白质功能的机制缺乏预测性的分子理解。该项目将提供有关氨基酸序列和环境如何调节蛋白质的能量格局、蛋白质结构或构象之间的映射以及控制其稳定性的热力学性质的生物物理信息。氨基酸序列、环境和能量环境之间的这种联系对于设计具有靶向行为的蛋白质的能力是必不可少的，例如功能、机械特性和寿命。此外，PI将开发一个项目，为加州大学伯克利分校生命科学的研究生和博士后提供广泛的职业接触、探索和经验。加州大学伯克利分校将设立一个新的专业人员驻场(PIR)计划，来自不同领域(工业和创业、教育和外展、政策和传播、学术和研究机构)的专业人员每年将在加州大学伯克利分校与学员和教职员工互动几天，让他们接触到来自不同职业道路的成功专业人员。这项研究的科学目标是利用单分子力学研究和氢交换技术来研究蛋白质折叠问题。这项工作的结果将加深我们对蛋白质折叠的理解，蛋白质折叠是氨基酸序列指导蛋白质能量格局(所有可接近构象的结构、能量和相互转化速率)的机制，这是现代分子生物学面临的主要挑战。在没有更好地了解这些特征是如何在蛋白质序列中编码的情况下，不断扩大的序列数据库继续隐藏着许多重要问题的答案。单分子蛋白质折叠研究的结果将产生可直接用于蛋白质折叠理论研究的观察物，实验将在与该领域的理论家的迭代合作中进行。机械应力在蛋白质功能和生物学中起着无处不在的作用，因此，除了对蛋白质折叠问题提供必要的洞察外，这项工作还将提供关于蛋白质机械稳定性的迫切需要的信息。该项目由分子和细胞生物科学部的分子生物物理学小组和物理系的生命系统物理计划联合资助。

A fundamental obstacle to understanding the rules of Life, is the lack of a predictive, molecular understanding of the mechanisms by which the genome encodes the function of a protein. This project will provide biophysical information on how the amino acid sequence and the environment tune a protein's energy landscape, the mapping between protein structure or conformation and thermodynamic properties which govern its stability. This connection between amino acid sequence, environment and energy landscape is imperative for the ability to design proteins with targeted behaviors such as function, mechanical properties, and lifetime. In addition, the PI will develop a program to provide broad career exposure, exploration and experience to graduate students and postdocs in the life sciences at UC Berkeley. A novel Professionals in Residence (PIR) program will be instituted, where professionals from diverse fields (Industry and Entrepreneurship, Education and Outreach, Policy and Communication, Academic and Research Institutes) will spend several days a year at UC Berkeley interacting with both trainees and faculty - exposing them to successful professionals from a variety of career paths.The scientific objective of this research is to investigate the protein-folding problem using single molecule mechanical studies and hydrogen exchange techniques. The results from this work will further our understanding of protein folding, the mechanism by which the amino acid sequence directs the energy landscape of a protein (the structures, energies, and rates of interconversion of all of the accessible conformations), a major challenge for modern molecular biology. Without a better understanding of how these features are encoded in a protein sequence, the expanding sequence databases continue to conceal the answers to many important questions. The results of the single-molecule protein folding studies will yield observables that can be used directly in theoretical studies of protein folding and the experiments will be carried out in an iterative collaboration with theoreticians in the field. Mechanical stress plays a ubiquitous role in protein function and biology, and therefore, in addition to providing needed insight into the protein-folding problem, this work will also provide much needed information about the mechanical stability of proteins.This project is jointly funded by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences and the Physics of Living Systems Program in the Division of Physics.