Collaborative Research: A General Approach to the Design of Tailor-Made Glycan Recognition Protein Modules.

蛋白质-碳水化合物相互作用在细胞生长和分化、信号转导、细胞凋亡和受精等生物学过程中起着重要作用。从分子识别的角度来看，聚糖是具有挑战性的配体，因为它们彼此之间的区别仅仅在于彼此的附着点或单个羟基的位置。此外，基于聚糖的生物聚合物具有柔韧性和高度水合性。该项目的目标是在分子水平上了解模型系统中蛋白质-聚糖的相互作用，并利用这些知识通过综合计算和实验策略开发新的聚糖识别蛋白。从天然的聚糖结合蛋白cyanovirin开始，我们将探索支持与目标聚糖并行高亲和力结合的序列空间，利用实验方面的定向进化，快速对接方法以及计算方面的显式溶剂分子动力学模拟。这一提议的广泛影响是双重的。首先，该项目采用高度跨学科的方法，为研究生和本科生提供丰富的培训经验。其次，pi参加在爱荷华州和亚利桑那州立大学的高中水平的推广活动。在亚利桑那州立大学，Ozkan和Ghirlanda参与了由CRESMET （http://cresmet.asu.edu/MSTF/index.shtml）运行的亚利桑那州立大学数学和科学教学研究员项目。该项目将凤凰城地区弱势学校的高中教师带到亚利桑那州立大学进行研究实习，并结合科学教育技术的强化培训，并通过校园访问在学校和大学之间建立融洽的关系。马古利斯创建了一个导师配对计划（http://mentor.chem.uiowa.edu/），通过向上发展计划，将代表性不足的高中生纳入研究小组。

Protein-carbohydrate interactions play an important role in several biological processes, such as cell growth and differentiation, signal transduction, apoptosis, and fertilization. From a molecular recognition perspective, glycans are challenging ligands, in that they differ from each other simply by the point of attachment to each other, or by the position of single hydroxyl groups. Further, glycan based biopolymers are flexible and highly hydrated. The objective of this project is to understand at the molecular level protein-glycan interactions in a model system, and to use this knowledge to develop novel glycan recognition proteins through an integrated computational and experimental strategy. Starting from a natural glycan binding protein, cyanovirin, we will explore the sequence space that supports high-affinity binding to the target glycan in parallel, utilizing directed evolution on the experimental side, and fast docking methods as well as explicit solvent molecular dynamics simulations on the computational side.The Broader Impact of this proposal is twofold. First, the project relies on a highly interdisciplinary approach, which offers students at the graduate and undergraduate level a rich training experience. Second, the PIs participate in outreach activities at the high school level both at Iowa and at ASU. At ASU, Ozkan and Ghirlanda participate with this project to the ASU Math and Science Teaching Fellows program run by CRESMET (http://cresmet.asu.edu/MSTF/index.shtml). The program brings high school teachers from disadvantaged schools in the Phoenix area to ASU for research internships combined with intensive training in science education techniques, and establishes a rapport between schools and university that continues through campus visits. Margulis has created a mentor matching program (http://mentor.chem.uiowa.edu/) that through the Upward Bound Program integrates underrepresented high school students in research groups.