The Evolution of Protein Dynamics

蛋白质动力学的演变

• 批准号: 0848902
• 负责人: Floyd Romesberg
• 金额: $ 40.5万
• 依托单位: The Scripps Research Institute
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0848902&HistoricalAwards=false
• 关键词: Evolution; Protein; Dynamics

In this award, funded by the Experimental Physical Chemistry program, Professor Romesberg from The Scripps Research Institute will investigate issues relating to the evolution of protein dynamics. Proteins have evolved to perform their various biological functions that enable life; however, little is understood about how the process of evolution builds proteins for specific functions. One function central to all proteins is molecular recognition - the ability of a protein to find its binding partners within the complex milieu of the cell. Perhaps the single most remarkable system where the evolution of biological molecular recognition may be studied is the immune system, where antibodies (Abs) that recognize virtually any foreign molecule (or antigen, Ag) may be evolved from precursor (or germline) Abs within days of first encounter. The fundamental hypothesis of the proposed research is that the immune system starts with flexible and conformationally heterogeneous germline Abs that can bind a wide range of Ags with an induced-fit mechanism, and then introduces mutations that evolve them into more rigid mature Abs that bind only their target Ag with a lock-and-key mechanism. Thus, Professor Romesberg proposes that during evolution, Abs are selected based in part on a dynamic property, i.e. flexibility. To test this hypothesis, a variety of modern biophysical techniques will be employed, including nonlinear ultrafast laser spectroscopy and NMR spectroscopy, to characterize Ab dynamics and Ag-binding as a function of the specific mutations introduced during evolution. While the proposed research is focused on Abs, it should have important ramifications for how molecular recognition is evolved in other systems, such as with enzymes and their substrates or inhibitors and with signaling cascades and their signaling molecules. In addition to participating in the community outreach programs already in place at TSRI, including hosting high school student interns, presenting seminars, and participating in a lecture series at the Reuben H. Fleet Science Center in San Diego, a summer program for high school educators will be developed to bring the proposed work to a larger audience. The broader impacts of the proposed research are to introduce today's younger scientists, as well as the general public in the San Diego area, to contemporary, interdisciplinary research rooted in the fundamentals of evolution.

在这个由实验物理化学项目资助的奖项中，来自斯克里普斯研究所的Romesberg教授将研究与蛋白质动力学进化有关的问题。蛋白质已经进化为执行其各种生物功能，使生命得以存在；然而，人们对进化过程如何构建特定功能的蛋白质知之甚少。所有蛋白质的核心功能之一是分子识别--蛋白质在复杂的细胞环境中找到结合伙伴的能力。也许研究生物分子识别进化的最显著的系统是免疫系统，在免疫系统中，识别几乎任何外来分子(或抗原，Ag)的抗体(Abs)可能在第一次相遇的几天内从前体(或生殖系)Abs进化而来。这项研究的基本假设是，免疫系统一开始是灵活的和构象不同的生殖系抗体，可以通过诱导适合机制结合广泛的AGs，然后引入突变，使它们进化成更刚性的成熟Abs，用锁和钥匙机制仅结合其靶标Ag。因此，Romesberg教授提出，在进化过程中，单抗的选择部分基于一种动态属性，即灵活性。为了验证这一假设，将使用包括非线性超快激光光谱和核磁共振光谱在内的各种现代生物物理技术来表征在进化过程中引入的特定突变的抗体动力学和Ag结合。虽然拟议的研究集中在抗体上，但它应该对分子识别如何在其他系统中进化产生重要的影响，例如与酶及其底物或抑制剂的分子识别，以及与信号级联及其信号分子的识别。除了参加TSRI已有的社区外展计划，包括接待高中生实习生、举办研讨会和参加圣地亚哥鲁本·H·弗利特科学中心的系列讲座外，还将为高中教育工作者制定暑期计划，将提议的工作带给更多的受众。拟议研究的更广泛影响是向当今年轻的科学家以及圣地亚哥地区的普通公众介绍植根于进化论基本原理的当代跨学科研究。