CAREER: Computational studies of dynamic molecular search mechanisms

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To date, research on molecular recognition has largely focused on structural properties of molecules such as arrangements of functional groups. Examples of how nature employs collective dynamics to enhance specificity are now emerging and leading to a shift from a static to a dynamic perspective. Interpretation and rational design of experiments to probe these novel mechanisms requires relating systems-level events to atomic-level ones and their associated changes in free energies. Computational tools for this purpose will be developed and applied to a paradigmatic system, the human protein O6-alkylguanine-DNA alkyltransferase (AGT). AGT repairs modified guanine and thymine DNA bases by flipping nucleotides into its active site and transferring alkyl groups irreversibly to cysteine. Extensive biochemical and structural data available make it ideal for computational investigations. Means for efficiently characterizing collective dynamics automatically and initiating transition path sampling simulations will be introduced and applied to the study of three mechanisms speculated to enable efficient detection of lesions in the genome: coupling of motions between different substrate degrees of freedom, partial nucleotide flipping for kinetic proofreading, and facilitated binding leading to apparent directional scanning along DNA. The research will promote application of state-of-the-art methods for studying activated dynamics to biomolecular systems, and their use to treat the dynamics of AGT and DNA will provide atomic-level insight into the kinetic strategies molecules use to control their interactions.Computational methods will be developed and applied to the study of AGT, a protein that is of fundamental interest because it repairs damaged genetic material. The project will provide insight into how molecules control their interactions with others, a process that is at the heart of much of modern chemistry and biology. This research will be coupled with creation of a "hands-on" computational curriculum that will foster interdisciplinary science and communication.