The primary goal of this project is to develop methods to predict structures of membrane proteins from their sequences and available experimental data and to use these methods to develop structural models of specific membrane proteins. The simplest structures we have been analyzing are a series of peptides (melittin, delta lysin, magainin, PGLa, and pardaxin) that form amphipathic a helices that aggregate in different ways dependent upon the environment surrounding the peptide. These studies involve combining computer graphics techniques with energy calculations by the program CHARMM. To test these methods we developed a model of the crystal structure of delta lysin. This peptide has been crystalized and the unit cell dimensions have been determined; however, its precise structure is not yet known. Magainin and PGLa are potent antimicrobial peptides found in Xenopous skin. The antimicrobial activity of these peptides and their ability to permeablize lipid vesicles and lyse cells is much greater when both peptides are present. We developed structural models of how magainin and PGLa can self aggregate and aggregate with each other in order to understand the molecular basis for this synergistic effect. We have also continued to develop structural models of larger integral membrane proteins. The protein families that we are currently analyzing are transmitter-activated channels (nicotinic acetylcholine, CABA, and glycine receptors), voltage activated channels (sodium, calcium, and potassium channels), receptors that activate G proteins (adrenergic, muscarinic acetylcholine, seritonin, dopamine, substance K, and opsin receptors), and gap junction channels.
