The Division of Materials Research and the Division of Molecular and Cellular Biosciences contribute funds to make this award. This award supports theoretical research and education in the field of molecular mechanisms of protein nucleic-acid interactions. Nucleic acids (DNA and RNA) and proteins are some of the fundamental molecules of living systems. In a living organism they perform their biological function based on their interactions with each other. The overarching goal of the research under this award is to develop theoretical models of the complex phenomena resulting from these interactions. The research will be in close collaborations with experimentalists resulting in immediate feedback between model building and experiments and thus leading to a deep understanding of the biological phenomena of interest based on molecular mechanisms. There are three specific phenomena that will be studied:
1. As cells repair damage to their DNA they have to clear the stretch of DNA to be repaired from associated proteins such as transcription factors and histones. For DNA mismatch repair this is the function of the protein complex MSH2/MSH6 which forms a sliding clamp on the DNA in the vicinity of a mismatch. Quantitative models developed under this award will reveal the detailed molecular mechanism underlying this clearing of DNA through binding of MSH2/MSH6. 2. When retroviruses, such as HIV, infect a cell, they use a special protein to 'soften' the secondary structures of their RNA genome and enable several molecular processes that are necessary for successful host infection. Under this award a quantitative model will be developed to explain how nucleocapsid and similar RNA binding proteins change the secondary structure of RNA molecules and its dynamics and how these structural changes affect the processes necessary for retroviral infection. 3. RNA molecules can be threaded through protein and artificial nanopores that are so small that only a single strand of the molecule can pass through them. Thus, the secondary structure of these molecules has to unravel in order for the molecule to pass through the pore. This makes nanopore translocation experiments a unique vehicle to study RNA secondary structure kinetics. However, this requires molecular scale models of RNA structure kinetics and interactions with the nanopore which will be developed under this award.
The research and educational activities will provide a highly interdisciplinary training to graduate and undergraduate students through various avenues such as direct involvement in the research and participation in biophysics courses and seminars. The scientific impact of the models developed under this award will be maximized by incorporating these models into existing or newly developed web servers.
NON-TECHNICAL SUMMARY
The Division of Materials Research and the Division of Molecular and Cellular Biosciences contribute funds to make this award. This award supports theoretical research and education in the physics of biological molecules. There are three major classes of molecules that life is based upon, namely proteins, nucleic acids (DNA and RNA), and lipids. These different types of molecules have their distinct roles, but in order for a living cell to function they all have to work together. The research under this award specifically focuses on the interplay between proteins and nucleic acid molecules. The overarching goal is to develop theoretical models of the complex phenomena that arise as proteins and nucleic acids interact. These models in turn will allow the interpretation of experiments and enable a deep understanding of diverse biological phenomena. The specific phenomena of interest here are how cells correct errors in their DNA in order to avoid cancer, how retroviruses (such as HIV) infect a host cell, and how RNA molecules pass through minuscule holes and reveal their dynamical properties.
The research and educational activities will involve training graduate and undergraduate students at the frontiers of research at the interdisciplinary interface between the life and the physical sciences. All projects will be performed in close collaborations with experimentalists thereby providing a unique training environment to the students involved in the research. In addition, the models developed in the course of this research will be disseminated through interactive web pages in order to enable their utility to as broad a group of users as possible.
