CAREER - Flexibility vs. Preorganization: Atomistic Simulations of Partner Recognition by Natively Unfolded Peptides

大部分蛋白质是天然未折叠的，或者缺乏明确的结构。这些蛋白质中的许多仅在与其伴侣蛋白结合时折叠，这表明了蛋白质-蛋白质识别的新范例。这种新的范式挑战了传统的假设，即如果蛋白质是预先组织的，那么它们会更快地结合它们的伴侣，在它们的未结合状态下采用与它们的结合状态相同的结构。这个CAREER项目将重新评估这一假设，通过比较天然未折叠肽与其精确的，预先组织的类似物的结合率，使用原子详细的计算机模拟。这种直接比较是无法通过实验室实验实现的。本研究的新方面是（a）使用加权系综方法将原子计算机模拟集中在涉及构象变化或结合伴侣形状变化的罕见结合事件的采样上，（B）其在分布式计算资源内的实现以显著增加该方法的计算范围，及（c）研究实际约束税率而不强迫事件发生的意图。该项目的结果将促进对分子识别基本原理的理解，并因此可以改进用于设计所选蛋白质-蛋白质相互作用的高度特异性抑制剂、分子传感器和分子开关的策略。随着现代研究越来越多的跨学科性质，学生必须学习如何向广大观众提供有效的科学演示。Chong博士设计并教授了一门本科课程，帮助学生通过整个学期的密集练习和反馈来开发有效的科学演示。在此经验的基础上，她将开发其他方法来帮助学生提高他们的口语技能。这些方法包括训练学生在五分钟内交流科学中的具体概念，并将这些演示打包成播客和数字视频。为了扩大这种培训的范围，Chong博士将鼓励全国各地的大学生在她将在全国会议上组织的比赛中制作这样的视频。本次比赛的目标包括：a）帮助大学生发展有效的沟通技巧; B）促进大学生，包括少数民族对科学的兴趣。最后，Chong博士将通过设计一门有效科学演示的研究生课程，将培训扩展到研究生。

A substantial fraction of proteins are natively unfolded, or lack well-defined structure. Many of these proteins fold only upon binding to their partner proteins, suggesting a new paradigm for protein-protein recognition. This new paradigm challenges the conventional assumption that proteins bind their partners more quickly if they are preorganized, adopting structures in their unbound states that are identical to structures in their bound states. This CAREER project will reassess this assumption by comparing the rates of partner-binding by natively unfolded peptides with their exact, preorganized analogues using atomically detailed computer simulations. Such direct comparison is not achievable by laboratory experiments. Novel aspects of this research are (a) the use of the weighted ensemble approach to focus atomistic computer simulations on the sampling of rare binding events that involve conformational changes, or changes in the shapes of the binding partners, (b) its implementation within distributed computing resources to dramatically increase the methodology's computational reach, and (c) the intention to study realistic binding rates without forcing the events to occur. Results from this project will advance the understanding of fundamental principles governing molecular recognition and could therefore improve strategies for designing highly specific inhibitors of chosen protein-protein interactions, molecular sensors, and molecular switches.Broader Impacts. With the increasingly interdisciplinary nature of modern research, it is essential for students to learn how to give effective scientific presentations to broad audiences. Dr. Chong has designed and taught an undergraduate course that helps students develop effective scientific presentations through intensive practice and feedback throughout the semester. Building on this experience, she will develop additional approaches for helping students improve their speaking skills. These approaches include training students to communicate specific concepts in science within five minutes and packaging these presentations into podcasts and digital videos. To broaden the outreach of this training, Dr. Chong will encourage undergraduates from institutions all over the country to create such videos in a contest that she will organize at a national conference. Goals of this contest include: a) to help undergraduates develop effective communication skills and b) to promote interest in the sciences among undergraduates, including minorities. Finally, Dr. Chong will extend the training to graduate students by designing a graduate course in giving effective scientific presentations.