CAREER: Structure, Dynamics, and Energetics of DNA Mismatch Recognition

Michigan State University, East Lansing MI

Investigators

Abstract

This investigator is interested in helping to broaden structural biology studies to address not only single molecules in aqueous environments but also large molecular complexes in heterogeneous environments. He approaches this area through modeling via computer simulations. For this project he has chosen as his focus the atomic details of the interactions between mismatch repair complexes and DNA. He will carry out his investigations with data from both the bacterial and eukaryotic complexes. He will address three key questions: 1.) How does the MutS protein differentiate defective DNA from regular DNA? 2.) How does binding of defective DNA lead to repair initiation? 3.) What is the molecular origin of specialization for different types of DNA defects in eukaryotic homologs of the MutHLS system? For the modeling, recently developed implicit solvent methods based on the generalized Born formalism will be used and developed further in the context of protein-DNA interactions in order to balance computational efficiency with a realistic description of the solvent environment. A second major component of this project is the introduction of computer simulation modeling as part of structural biology curricula directed at biology students. Implicit descriptions of biological environments are particularly attractive for education because such models greatly simplify and accelerate atomic-level modeling. In addition, the PI will work on simplifying interfaces for advanced molecular modeling and analysis tasks, thus allowing biology students to focus on applications of the techniques to biological questions rather than on the sometimes overwhelming technical details of the simulation methodologies. Cells normally repair errors in genetic material efficiently. When errors are not repaired, however, the resulting defects can cause profound problems in cellular metabolism. Obviously, repair mechanisms are of utmost importance to all organisms. The functioning of one specific repair mechanism will serve as the subject of this attempt to improve structural biological modeling via computer simulation and to make such modeling more accessible to biology students through specialized courses and computer-user interfaces.