The Evolution of Protein Dynamics

在这个由实验物理化学计划资助的奖项中，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。蛋白质已经进化到执行各种生物功能，使生命;然而，很少有人了解进化过程如何构建蛋白质的特定功能。 所有蛋白质的一个核心功能是分子识别-蛋白质在细胞复杂环境中找到其结合伴侣的能力。 也许可以研究生物分子识别进化的最显著的系统是免疫系统，其中识别几乎任何外来分子（或抗原，Ag）的抗体（Ab）可以在第一次遇到的几天内从前体（或种系）Ab进化而来。 这项研究的基本假设是，免疫系统从柔性和构象异质性的种系抗体开始，这些抗体可以通过诱导配合机制结合各种各样的抗原，然后引入突变，使它们进化成更刚性的成熟抗体，这些抗体通过锁和钥匙机制仅结合其靶抗原。 因此，Romesberg教授提出，在进化过程中，Abs的选择部分基于动态特性，即灵活性。 为了验证这一假设，将采用各种现代生物物理技术，包括非线性超快激光光谱和NMR光谱，以表征Ab动力学和Ag结合作为进化过程中引入的特定突变的函数。 虽然拟议的研究重点是抗体，但它应该对分子识别如何在其他系统中进化产生重要影响，例如酶及其底物或抑制剂以及信号级联及其信号分子。 除了参加TSRI已经实施的社区外展计划，包括接待高中生实习生，举办研讨会，并参加鲁本H。舰队科学中心在圣地亚哥，一个夏季计划的高中教育工作者将开发，使拟议的工作，以更大的观众。拟议的研究的更广泛的影响是介绍今天的年轻科学家，以及在圣地亚哥地区的公众，以当代，跨学科的研究植根于进化的基本原理。

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.