This research project aims to understand the role of structural plasticity in mediating binding specificity and affinity between protein domains and flexible ligands. The specific recognition of a ligand is the key function of many proteins, and forms the basis of the extensive networks that coordinate the activities of central biological processes. In many biological contexts, a protein domain functionally recognizes a family of related ligands while discriminating against structurally similar ligands. The hypothesis to be tested is that the recognition of related ligands is more structurally diverse than can be inferred from a single structure of a protein-ligand complex. The rigorous biochemical and structural analysis of the ensemble of conformations adopted at biomolecular interfaces that is part of this research program will contribute to our understanding of the underlying mechanisms of ligand-binding specificity. Furthermore, this knowledge will provide insights for computational efforts aimed at understanding and predicting ligand-binding specificity.
This work will significantly advance our understanding of the mechanisms that confer specificity in protein-ligand interactions, which are essential to a wide variety of biological functions. In addition, the structural and biochemical data will complement ongoing computational studies by others that seek to model protein-ligand interactions. Furthermore, the program outlined here promotes teaching, training and learning while advancing scientific discovery. These activities occur through a well-designed and thoughtful postdoctoral fellow and graduate student mentoring program, as well as through teaching innovations in the undergraduate classroom. The PI also participates in several programs to increase the participation of under-represented groups, including women and minorities in science, ranging from faculty, postdoctoral fellow and graduate student career mentoring to tailoring the graduate curriculum to facilitate recruitment and retention of under-represented minorities. This program supports the use of our regional high field NMR facilities, including 800 and 900 MHz instruments equipped with cryogenic probes. In addition to the normal avenues of dissemination of research findings, including peer-reviewed publication and presentations at scientific meetings, the PI participates in community outreach through science activities at local schools and as a CU Wizard, orchestrating a community science show.