Plasticity in the Recognition of Flexible Ligands

本研究旨在了解结构可塑性在调节蛋白质结构域和柔性配体之间的结合特异性和亲和力中所起的作用。配基的特定识别是许多蛋白质的关键功能，并形成协调中央生物过程活动的广泛网络的基础。在许多生物学背景下，蛋白质结构域在功能上识别一系列相关的配体，同时区分结构相似的配体。需要检验的假设是，与蛋白质-配体复合体的单一结构相比，相关配体的识别在结构上更加多样化。作为本研究计划的一部分，对生物分子界面所采用的构象系综进行严格的生化和结构分析将有助于我们理解配体结合专一性的潜在机制。此外，这一知识将为旨在理解和预测配体结合特异性的计算工作提供见解。这项工作将极大地促进我们对蛋白质-配体相互作用中赋予特异性的机制的理解，这是广泛的生物功能所必需的。此外，结构和生化数据将补充其他人正在进行的计算研究，这些研究试图对蛋白质-配体相互作用进行建模。此外，这里概述的计划在促进科学发现的同时促进了教学、培训和学习。这些活动通过精心设计和深思熟虑的博士后研究员和研究生指导计划以及本科生课堂的教学创新来进行。国际学生联合会还参与了几个方案，以增加代表不足群体的参与，其中包括科学界的妇女和少数群体，从教员、博士后研究员和研究生职业生涯指导到调整研究生课程以促进招聘和留住代表不足的少数群体。该计划支持使用我们的地区性高场核磁共振设施，包括配备低温探头的800和900 MHz仪器。除了传播研究成果的正常途径，包括同行评议的出版物和在科学会议上的陈述外，PI还通过在当地学校的科学活动参与社区推广活动，并作为CU向导，策划社区科学表演。

This research project aims to understand the role of structural plasticity in mediating binding specificity and affinity between protein domains and flexible ligands. The specific recognition of a ligand is the key function of many proteins, and forms the basis of the extensive networks that coordinate the activities of central biological processes. In many biological contexts, a protein domain functionally recognizes a family of related ligands while discriminating against structurally similar ligands. The hypothesis to be tested is that the recognition of related ligands is more structurally diverse than can be inferred from a single structure of a protein-ligand complex. The rigorous biochemical and structural analysis of the ensemble of conformations adopted at biomolecular interfaces that is part of this research program will contribute to our understanding of the underlying mechanisms of ligand-binding specificity. Furthermore, this knowledge will provide insights for computational efforts aimed at understanding and predicting ligand-binding specificity. This work will significantly advance our understanding of the mechanisms that confer specificity in protein-ligand interactions, which are essential to a wide variety of biological functions. In addition, the structural and biochemical data will complement ongoing computational studies by others that seek to model protein-ligand interactions. Furthermore, the program outlined here promotes teaching, training and learning while advancing scientific discovery. These activities occur through a well-designed and thoughtful postdoctoral fellow and graduate student mentoring program, as well as through teaching innovations in the undergraduate classroom. The PI also participates in several programs to increase the participation of under-represented groups, including women and minorities in science, ranging from faculty, postdoctoral fellow and graduate student career mentoring to tailoring the graduate curriculum to facilitate recruitment and retention of under-represented minorities. This program supports the use of our regional high field NMR facilities, including 800 and 900 MHz instruments equipped with cryogenic probes. In addition to the normal avenues of dissemination of research findings, including peer-reviewed publication and presentations at scientific meetings, the PI participates in community outreach through science activities at local schools and as a CU Wizard, orchestrating a community science show.