Influenza hemagglutinin (HA) serves as a model system for the study of protein mediated membrane fusion. It is the most important virulence factor for influenza viruses and is potentially a very attractive target for novel therapeutic agents. Successfully targeting the inhibition of pH-induced large-scale conformational changes that lead to membrane fusion could effectively prevent host cell infection. Antiviral agents targeting other viral proteins are currently used to treat infections only after the appearance of symptoms. Given that HA is the canonical type I glycoprotein, mechanistic studies of HA would contribute to our understanding of the functional mechanisms of other viral fusogens as well. Our long-term goal is to develop a computational framework for the rational design of novel therapeutic agents targeting the conformational rearrangements that drive the influenza HA-mediated membrane fusion process. Our overall objective here is to accurately describe, at an atomic and thermodynamic level, the conformational and structural dynamics of HA under physiological conditions and in the presence of candidate drugs to decipher the mechanism of HA activation and inhibition due to pH change and drug binding, respectively. While current paradigm in biomolecular simulation studies is dominated by simplistic models such as coarse graining (for large-scale conformational changes) and docking (for drug-protein interaction) and the more accurate and reliable all-atom molecular dynamics (MD) simulations are limited to relatively short timescales, we propose to use microsecond-level all-atom MD simulations in conjunction with statistical mechanics based enhanced sampling techniques to provide a detailed, reliable account of the HA mediated membrane fusion mechanism and its interactions with candidate drugs. The rationale for the proposed research is that, if the molecular basis of HA-mediated membrane fusion is better understood, we can design more potent therapeutic agents to combat influenza viruses. The proposed research will shed light on the conformational landscape of a major influenza virulence factor, establishing a robust rational framework for the design of novel therapeutic agents that can inhibit protein-mediated membrane fusion and prevent influenza viral infections. This project will provide graduate and particularly undergraduate students at the University of Arkansas with opportunities to work in an interdisciplinary area of biomedical research.
Influenza hemagglutinin protein serves as a model system for the study of protein mediated membrane fusion and is an import target for novel therapeutic agents. By employing accurate models of this protein and characterizing its structural dynamics, this project will elucidate the molecular mechanism of hemagglutinin pH-induced conformational changes and establish the groundwork for rational design of novel drugs targeting this protein.
