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.
The outcome of this project is a set of theories that provide insights into the fundamental physical principles that govern the structure formation, dynamics and functioning of biological macromolecules. This project used the 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. Specifically, the PI's group: 1) established a mathematical transformation that met the long-sought goal to decode the mechanical fingerprints of macromolecules, 2) developed a theory that enables the determination of the kinetics and energetics of biomolecular folding and binding, 3) developed a theory that resolved a central controversy in single-molecule force spectroscopy, 4) developed a theory of the extension-clamp manipulation mode, which allows access to conformational transitions that are not accessible by other methods, 5) formulated an analytical theory of force spectroscopy of conformational transitions that proceed through an intermediate state, 6) identified the physical mechanism that enables remote DNA segments to find each other in a crowded cell to establish critical genomic interactions. The PI developed and taught the "Fundamentals of Biological Physics" course that teaches how quantitative models derived from statistical physics can be used to build a quantitative, intuitive understanding of biological phenomena. Through her meetings with the general public as a representative at the Physics Café, organized by the Aspen Center for Physics, and other outreach activities, the PI has demonstrated her commitment to the broader effort to recruit, encourage and nurture scientists in biological physics from a diversity of backgrounds and representing all segments of our society.
