Linda Jen-Jacobson

The long-range objective of our research is to gain insight into the molecular determinants for high DNA site selectivity by proteins. Our strategy uses the conceptual and analytical methods of biophysics and structural biochemistry in combination with the manipulation methods of synthetic chemistry and of molecular genetics, and emphasizes the concerted use of a number of tools. We are currently combining high resolution "structural perturbation" methods with isothermal titration calorimetry to obtain complete thermodynamic profiles (i.e., changes in enthalpy, entropy, heat capacity) for protein-DNA complex formation, together with computational modeling to complement our interpretations. Some of our current work focuses on the thermodynamic consequences of molecular strain, experimental measurement of solvation changes upon binding, and the molecular properties of mutant proteins with reduced specificity.

Our ongoing principal goal is to adduce general principles applicable to most or all sequence-specific DNA-binding proteins. Our work points to the importance of time-dependent (dynamic) characteristics of protein-DNA complexes, including binding-dependent conformational transitions in the proteins and DNA and configurational (conformational and vibrational) fluctuations in the protein-DNA complexes, so we are pursuing spectroscopic methods (Nuclear Magnetic Resonance and Electron Spin Resonance) that inform us about these dynamics. A profound understanding of these basic physicochemical principles and their applications is what we will ultimately need to develop methods for knowledge-based drug design and design of macromolecules to fulfill specific biological functions.