INTELLECTUAL MERIT: This research program aims to use recently developed knowledge of electrostatics in aqueous media to understand and control complex biological systems governed by a hierarchy of interactions, of which electrostatics is only one part. The aim is to go beyond academic, prototypical electrostatic problems, and engage outstanding unsolved problems in biology. In biological systems, electrostatics coexists with other interactions such as the hydrophobic effect, hydrogen bonding, and geometric/osmotic effects. The proposal addresses three unsolved problems for which such hybrid interactions are essential. First is the formation of complexes of antimicrobial proteins (i.e., lysozyme) with oppositely charged polyelectrolyte (i.e., F-actin) to understand and then control the tendency to form stable complexes. In addition to its potential for biomedical impact, this study is motivated by basic questions about the interactions between periodic charge-densities with different periodicities. Second is a set of X-ray studies of mixtures of model lipid vesicles and pore-inducing TAT (trans-acting activator of transcription) proteins. This section will include studies of the particular role of the positively charged amino acids arginine vs lysine (which seems to go beyond the role of electrostatics to some other mechanism) and include exploratory studies on the ability of TAT to carry cargo across a membrane. The third major activity is a study of synthetic pore-forming antimicrobial compounds synthesized by a collaborator at the University of Massachusetts. X-ray scattering will be used to measure pore structure as a function of concentrations in model membranes and the results will be compared to bacterial response for different variants of the antimicrobial compound.
BROADER IMPACTS: Most interactions of biological macromolecules involve forces of several types. The proposal attempts to understand the resultant effect of these hybrid forces in complex systems. The mode of action of membrane pore forming peptides, especially the antimicrobial peptides, is not yet understood. This project seeks fundamental understanding of how naturally occurring and synthetic antimicrobial peptides and other membrane pore formers work. The project provides for highly interdisciplinary training of students and postdoctorals who will gain experience not only in the basic physics and physical chemistry of biological systems but who will also become familiar with the resources of national and international light source facilities. The PI has an excellent record of involving undergraduates in his research program, many of whom are coauthors on publications. He plans to continue to host undergraduate researchers and to give these students the opportunity to experience a research environment that leads many to continue on a research pathway in graduate and professional school. The PI is anxious to expand his outreach activity to the K-12 educational sector beyond the typical "one-shot" university Open House programs and to develop a more enduring relationship with K-12 students and teachers. To this end he has established a partnership with a local middle school, and he will make repeated visits to the school with the goal of "making the strange familiar and the familiar strange" through a series of presentations and activities that give the students and teachers hands-on experience with the properties of interesting materials.
