Cooperative Interactions in Proteins

Johns Hopkins University, Baltimore MD

Investigators

Abstract

Protein-protein interactions are essential to all cellular processes and the mechanisms of bacterial and viral infection. Often, those interactions trigger conformational changes at locations away from the binding epitopes that modify or elicit new functionalities in one or both proteins. How are these signals transmitted from one point to another in a protein? Can critical points that will disable signal transduction be identified? Can these points be targeted by small molecular weight inhibitors? The answer to these questions will provide a fundamental understanding of protein function and new ways of engineering molecules that can modulate those interactions. Those are the long-range objectives of this project. This project will focus on the HIV protein Nef, a protein known to interact with different cell proteins in a concerted allosteric way. The binding of Nef to different partners is allosterically modulated by the binding to previous ones in a process in which the weakly structured regions play key roles. This research project will provide a new understanding of protein-protein interactions and the effects of those interactions in regions distal from the binding site. In addition to the intellectual merit, the broader impact resulting from this research includes different fronts. At the practical level, it provides new strategies for designing small molecules that can inhibit protein-protein interactions or block the transmission of allosteric effects through the protein structure. These intellectual advances may eventually lead to important drug design applications. While guidelines for developing enzyme inhibitors are widely available, it must be noted that precise guidelines for the design of small molecules that inhibit protein-protein interactions or disable allosteric effects are non-existent. The broader impact is, however, not limited to the potential applications of the scientific discoveries. Graduate students and undergraduate students have benefited from this project by the incorporation of these state-of-the-art topics in their educational curriculum. Also this project has allowed and will continue to encourage the participation of undergraduates, including female and minorities, in different experimental and computational aspects of the research.