PECASE: Probing protein surfaces using multiple solvent crystal structures

提案标题：PECASE：使用多溶剂晶体结构探测蛋白质表面机构：北卡罗来纳州州立大学本次PECASE奖支持的研究目的是使用新型多溶剂晶体结构方法研究蛋白质上配体结合位点的特征。这个想法是解决不同蛋白质在各种有机溶剂中的晶体结构，以绘制它们的结合表面。该研究将重点关注与不同类型配体相互作用的五种代表性蛋白质。前提是溶剂分子具有与较大配体的组成部分共同的特征，并且主要在作为结合位点进化的区域中结合。同时，本体溶剂相对于水溶液的性质的变化提供了蛋白质环境的变化。对这些多种环境中的蛋白质晶体结构的分析可用于描绘能够适应变化的结构组分。是否存在与结合位点的形状、动力学、静电和疏水含量的巨大差异无关的水合、可塑性和疏水暴露表面的共同模式？配体的类型在多大程度上决定了蛋白质的表面性质，动力学如何影响结合位点的特征？这些问题的答案是至关重要的，我们对蛋白质和蛋白质配体相互作用的基本理解，并最终将有助于弥合差距之间的差距，我们观察到的实验和我们可以预测的第一原理。更广泛的影响：模型的建立和晶体结构的细化将被整合到蛋白质结构和功能的本科课程，并进入研究生课程的大分子建模。参加这些课程的学生将与研究团队密切合作，完成结构的改进。因此，该项目的科学目标将在一个教育框架内实现，该框架旨在提高学术阶梯几个阶段的个人的知识和研究经验。该项目旨在1）减少学生教学和研究经验之间的差距，2）让大量学生接触指导前沿研究的问题，同时为学生提供课堂上讨论的概念的说明，3）激发本科生，特别是女性和拉丁美洲学生的兴趣，可能永远不会有动机询问课堂之外的研究，4）开发一个激励博士后和研究生成为优秀教师的过程。这个项目最初是作为一个职业奖资助的，并于2004年9月转换为总统工程师和科学家早期职业奖（PECASE）。

Proposal Title: PECASE: Probing protein surfaces using multiple solvent crystal structuresInstitution: North Carolina State UniversityThe objective of the research supported by this PECASE award is to investigate the character of ligand binding sites on proteins using the novel multiple solvent crystal structures method. The idea is to solve the crystal structures of different proteins in a variety of organic solvents in order to map their binding surfaces. The study will focus on five representative proteins that interact with different types of ligands. The premise is that the solvent molecules have characteristics in common with component parts of larger ligands and bind primarily in areas that evolved as binding sites. At the same time, changes in the properties of the bulk solvent relative to an aqueous solution provide changes to the protein environment. Analysis of the protein crystal structures in these multiple environments can be used to delineate structural components that are able to adjust to the change. Are there common patterns of hydration, plasticity and hydrophobic exposed surfaces that are independent of vast differences in shape, dynamics, electrostatic and hydrophobic content of the binding sites? To what extent does the type of ligand determine the surface properties of proteins, and how do dynamics affect the binding site features? Answers to these questions are critical to our basic understanding of protein-protein and protein-ligand interactions and will ultimately help to bridge the gap between what we observe experimentally and what we can predict from first principles.Broader impact: Model building and refinement of the crystal structures will be integrated into an undergraduate course on protein structure and function and into a graduate course on macromolecular modeling. The students taking these courses will work closely with the research team to complete the refinement of the structures. Thus, the scientific objectives of this project will be accomplished within an educational framework designed to enhance the knowledge and research experience of individuals from several stages of the academic ladder. This project aims to 1) decrease the gap between teaching and research experiences of the students, 2) expose a large number of students to the questions guiding cutting edge research while offering students an illustration of the concepts discussed in class, 3) spark an interest in undergraduates, particularly women and Latino students, that might never have had the motivation to inquire about research outside of the classroom and 4) develop a process by which post-docs and graduate students are motivated to be excellent teachers.This project was originally funded as a CAREER award, and was converted to a Presidential Early Career Award for Engineers and Scientists (PECASE) award in September 2004.