CAREER: Theoretical Approaches to Single-molecule Biophysics

这个职业项目的目标是了解在单分子水平上支配生物大分子的结构、形成和功能的基本物理原理。其策略是利用非平衡物理学的强大解释能力来解决分子和细胞生物学中原本难以解决的问题，并反过来通过在单个生物分子水平上探索生物过程来激发新的物理概念。该研究计划包括四个相互关联的项目：(1)从单分子操作揭示活细胞过程的机制。该项目解决了从实验结果中提取新信息这一具有挑战性的任务。(2)分析实验变量对单分子操作的影响。该项目将建立从感兴趣的生物分子的信息中分离出实验装置中的因素的方法。(3)阐述了单分子力谱的多态理论。该项目将能够研究和预测在更高的复杂性水平上可能出现的新现象。(4)理解多维自由能景观在复杂生物分子机械展开中的作用。这一方法将有助于设计研究复杂生物分子中二级和三级结构的实验。这一研究计划将为实现PI将单分子生物物理理论扩展到细胞水平和访问活细胞的机械的长期目标奠定基础。卓越教育的基础将建立在以下贡献之上。(1)将研究活动纳入本科课程，旨在模仿研究人员撰写可发表的研究论文并与同行一起为其手稿内容辩护的过程。(2)有可能改变人们学习科学方式的教学创新。这些措施包括使用个人反应系统点击器，这是现有的最强大和最灵活的学生反应系统，以及越来越多地使用计算机模拟来创建交互式“虚拟”物理实验。3)将代表性不足的群体纳入本科生的研究渠道。加州州立大学圣马科斯分校将成为主要合作伙伴，努力将尖端生物物理学纳入教学大学的课程。由于推广仍然是物理界的一项重大挑战，将利用人们对生命系统的广泛兴趣来确保这一挑战得到满足。国际物理学会认为，生物物理必须成为所有物理系的主流课程。设计的创新课程与研究、培训和推广活动相结合，将能够培训一支新的科学家队伍，他们在高级物理和计算方面的能力与生化反应、实验方案和生物数据库方面的能力相同。这一方法将被用作一种手段，以建立国内和国际对生物物理和物理前沿研究的认识，并使加州大学圣迭戈分校成为将物理学的原理、语言和工具与生物学相结合的世界领先者，从而在我们对生命过程的理解方面产生一场革命。该项目由分子和细胞生物科学部的分子生物物理学和物理学部的生命系统物理学项目共同支持。

The objective of this CAREER project is to understand the fundamental physical principles that govern the structure formation and functioning of biological macromolecules at the single-molecule level. The strategy is to use the great explanatory power of non-equilibrium physics to tackle otherwise intractable problems in molecular and cell biology, and conversely to motivate new physical concepts through the exploration of biological processes at the level of individual biomolecules. The research plan includes four interrelated projects: (1) Revealing mechanisms of living cell processes from single-molecule manipulations. The project addresses the challenging task of extracting novel information from experimental outputs. (2) Analyzing the effect of experimental variables on single-molecule manipulations. The project will establish the ways to disentangle the factors in the experimental setup from the information about the biomolecule of interest. (3) Formulating multistate theory of single-molecule force spectroscopy. This project will enable the study and prediction of new phenomena that can emerge at higher levels of complexity. (4) Understanding the role of multidimensional free energy landscapes in the mechanical unfolding of complex biomolecules. This approach will help design experiments that examine secondary and tertiary structure in complicated biomolecules.This research plan will build a foundation for achieving the PI's long-term goals of extending single-molecule biophysical theory to the cellular level and accessing the machinery of a living cell. The foundation for excellence in education will be built upon the following contributions. (1) Incorporating research activities into undergraduate courses, which are designed to mimic the processes an investigator undertakes in writing a publishable research paper and defending the content of their manuscript with peers. (2) Innovations in teaching that have the potential to transform how people learn science. These include the use of Personal Response System clickers, the most powerful and flexible student response system available, as well as making increasing use of computer simulations for creating interactive "virtual" physics experiments. 3) Bringing underrepresented groups into the research pipeline at the undergraduate level. California State University San Marcos will be the lead partner in efforts to extend leading-edge biological physics into the curriculum at teaching universities. As outreach remains a significant challenge for the physics community, advantage will be taken of the widespread interest in living systems to ensure this challenge has been met. The PI believes that biological physics must become a mainstream course in all physics departments. The designed innovative curriculum, integrated with research, training and outreach activities, will enable training of a new cadre of scientists equally competent in advanced physics and computation as in biochemical reactions, experimental protocols and biological databases. This approach will be used as a means to create a national and international awareness of biological physics and physics frontiers research, and to make UCSD the world leader in combining the principles, language and tools of physics with those of biology, so as to engender a revolution in our understanding of living processes. This project is jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences and by the Physics of Living Systems program in the Physics Division.