The Division of Materials Research and the Chemistry Division contribute funds to this award that supports theoretical research and education towards developing models for the interactions within nucleic acid and protein complexes. All living organisms use three main classes of biomolecules as their building blocks, nucleic acids (DNA and RNA), proteins, and lipids. Like Lego® pieces, these building blocks can be combined in myriads of different ways to give rise to all the complexities of living organisms. However, the rules by which these building blocks fit together (interact) are not well understood. The goal of this project is to develop mathematical models that describe the interactions of two of these building blocks, namely nucleic acids and proteins.
Such mathematical models offer two advantages: i) They allow a better understanding of how living organisms work, ultimately improving our ability to correct instances when they do not work, i.e., diseases. ii) They allow these natural molecules to be assembled in new ways in engineered systems to provide completely new functionality. In developing these models, the research team works closely with collaborators performing experiments on real systems to test and improve the models. To be specific and to address both of the goals presented above, one subproject focuses on how the interactions between the nucleic acid RNA and proteins guide the formation of the outer shell of viruses in infected cells, while the other subproject focuses on dynamic human-engineered DNA nanostructures called DNA origami that one day could form the basis of nanorobots.
In addition to the development of models that will improve understanding of diseases and enable novel engineering applications, the project will also train the next generation of researchers at the interface between life and physical sciences through their involvement in research, coursework, and seminars. This is important since Biology and Medicine on one side, and Physics, Mathematics, and Engineering on the other side traditionally use rather different languages and approaches; addressing the complex problems in Biology and Medicine today needs the more mathematical approaches that quantitative fields offer, and thus "bilingual" scientists who understand and speak the language of both are urgently needed.
The Division of Materials Research and the Chemistry Division contribute funds to this award that supports theoretical research and education towards developing models for the interactions within nucleic acid and protein complexes. In a cell, proteins, RNA and DNA interact with each other in a highly controlled fashion. The ability to reproducibly form specific complexes from these molecules also enables their use in creating man-made nanoscale devices. In this project, quantitative models of the interactions within such complexes will be developed. Quantitative models are crucial for understanding biological functions of biomolecular complexes, for interpreting experiments on such biomolecular complexes, and for designing novel complexes. All activities are performed in close collaboration with experimentalists.
The work in this project is divided into two main threads, one addressing interactions in natural biomolecular complexes and one addressing engineering man-made biomolecular complexes. The focus of the first subproject is on describing the interaction of double-stranded RNA binding proteins with RNA. Since these proteins are specific to double-stranded RNA, their binding to a given RNA molecule depends on the intramolecular interactions of the RNA molecule. One of the main goals of the project is the development of a model that can predict for arbitrary RNA molecules how strongly and at which locations a double-stranded RNA binding protein will bind. This will build upon the research team's previous experience and will result in a complete modeling framework for both of the common classes of RNA binding proteins. One important application of such a model is understanding the mechanism by which specific interactions between coat proteins and single-stranded RNA genome guide the assembly of the viral shell in certain RNA viruses. The other thread of the project focuses on developing models of dynamic DNA origami structures including those that incorporate functional mechanical elements, such as nucleosomes or RNA molecules. Such structures can be used to provide information on their immediate environment, perform functions such as drug delivery, and provide insight into the mechanical properties of biomolecules attached to them.
In addition to the development of models that will improve understanding of diseases and enable novel engineering applications, the project will also train the next generation of researchers at the interface between life and physical sciences through their involvement in research, coursework, and seminars. This is important since Biology and Medicine on one side, and Physics, Mathematics, and Engineering on the other side traditionally use rather different languages and approaches; addressing the complex problems in Biology and Medicine today needs the more mathematical approaches that quantitative fields offer, and thus "bilingual" scientists who understand and speak the language of both are urgently needed.
