CAREER: Molecular heterogeneity and the regulation of cell adhesion by force

职业：分子异质性和细胞粘附力调控人体内细胞之间的所有密切接触都涉及被称为粘附蛋白的特殊分子。这些分子参与传递信号，例如将免疫细胞招募到炎症部位，对组织的发育和维持至关重要。当这些蛋白质与它们的目标结合时，它们感受到的机械力可以极大地改变它们的行为，控制这种结合在断裂前的持续时间。在许多情况下，这种调节是违反直觉的，更大的张力导致更长的键寿命，并且潜在的微观机制知之甚少。本项目旨在通过理论和计算来研究这些机制，创建分析实验数据的通用方法，以阐明各种生物环境下粘附的分子细节。重点将放在蛋白质的异质性上，即粘附键可能呈现的不同结构状态，每种状态对施加的力都有自己的特征反应。该项目将通过BIOREPS（生物物理研究问题集）计划将前沿生物物理学研究融入本科教育。本科生物物理学课程的学生将把最近备受瞩目的研究论文转化为问题集，并发布在一个开放的在线数据库中。这些活动将使学生在科学教学和交流方面获得宝贵的经验。由此产生的数据库将成为一种独特的资源，可供所有寻找研究型课程材料的教育工作者使用。本项目的研究策略基于以下假设：张力对粘附蛋白键的调节可以通过表征其异质构象状态来解释，并解决蛋白质在不同力条件下如何在状态之间切换。该项目将直接从单分子力谱实验收集的数据中识别和描述键的多种构象状态。该项目将开发新的理论方法，弥合实验测量和粘附的微观机制之间的鸿沟，以克服从数据中破译分子细节的挑战。该项目还将开发基于结构的模型，将特定系统中可观察到的键动力学与张力引起的蛋白质构型和键能变化联系起来。数据分析和模型开发的并行关注为发现提供了一个全面的框架，利用了实验和理论之间的相互反馈。这项研究将为粘附提供直接的见解，但也有助于开发新的和更有信息的实验方案。

CAREER: Molecular heterogeneity and the regulation of cell adhesion by forceAll close contacts between cells inside the human body involve specialized molecules known as adhesion proteins. These molecules participate in transmitting signals, for example recruiting immune cells to the sites of inflammation, and are critical to the development and maintenance of tissues. The mechanical forces that these proteins feel when they bind to their targets can dramatically alter their behavior, controlling how long the bond endures before breaking. In many cases this regulation is counterintuitive, with larger tension leading to longer bond lifetimes, and the underlying microscopic mechanisms are poorly understood. This project aims to investigate those mechanisms through theory and computations, creating general methods for analyzing experimental data that will elucidate the molecular details of adhesion in a variety of biological contexts. The focus will be on protein heterogeneity-the diverse structural states which adhesion bonds can assume, each with its own characteristic response to applied forces. The project will integrate cutting-edge biophysics research into undergraduate education through the BIOREPS (BIOphysical REsearch Problem Set) initiative. Students in an undergraduate biophysics course will transform recent high-profile research articles into problem sets published in an open online database. These activities will give students valuable experience in scientific pedagogy and communication. The resulting database will become a unique resource, available to all educators looking for research-based course materials. This project's research strategy is based on the following hypothesis: the regulation of adhesion protein bonds by tension can be explained by characterizing their heterogeneous conformational states, and resolving how the protein switches between states under various force conditions. This project will identify and describe the multiple conformational states of the bonds directly from data gathered by single-molecule force spectroscopy experiments. This project will develop new theoretical approaches that bridge the divide between experimental measurements and the microscopic mechanisms of adhesion to overcome the challenge of deciphering the molecular details from the data. This project will also develop structure-based models that relate observable bond dynamics in specific systems to tension-induced changes in protein configuration and bond energies. Parallel focus on data analysis and model development provides a comprehensive framework for discovery, drawing on the mutual feedback between experiment and theory. The research will provide direct insights into adhesion, but also aid the development of new and more informative experimental protocols.