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Cellular Regulation by Reversible Macromolecular Associations

Biology is a dynamic process. Among the myriad array of reversible association reactions that constitute life as we know it, small molecules bind to proteins, proteins self-associate or bind to other
proteins, proteins bind to DNA and RNA changes conformation in elaborate signaling and regulatory cascades. For example, electrostatic interactions mediate both the binding of proteins to DNA
and the folding of RNA. DNA binding by proteins may be competitively regulated by other proteins that mimic the electrostatic character of DNA. What is common to these processes is the
physical chemistry that underlies these interactions. Our laboratory seeks to understand the following questions by combining quantitative analysis with innovative approaches.

How does RNA fold?

Although RNA is an informational intermediate in the central dogma, much of its biological function requires it to fold into unique three dimensional structures. However, large RNA molecules often
must navigate tortuous kinetic pathways to achieve their biologically active structure. Our group utilizes rapid kinetics that report the time evolution of RNA structure with single nucleotide
spatial and millisecond time resolution in conjunction with global and single molecule measures to illuminate RNA folding pathways.

How do proteins recognize specific sequences of DNA?

Proteins use what is termed ‘direct’ and ‘indirect’ readout to discern specific DNA sequences from the bulk of a genome. Direct interactions are noncovalent bonds between the two macromolecules. Indirect readout refers to changes in the structure and/or dynamics of the binding protein or DNA that regulate the interaction. Studies of the E2 protein from the human papillomavirus seek to
understand the relative contributions of direct and indirect readout and their role in mediating the viral life cycle and its relationship to cancer. Studies of the TATA Binding Protein (TBP) and its
associated factors being carried out in collaboration with departmental colleague Ian Willis seek to understand the contributions of direct and indirect readout to the initiation and regulation of
gene transcription in eukaryotes.

How do proteins mimic DNA?

Departmental colleague John Blanchard recently solved the structure of a new family of proteins some of which appear to function by mimicking the structure and electrostatic surface of DNA.
Collaborative studies aim to understand the biophysics of DNA mimicry by proteins and understand their role in cellular regulation.