In collaboration with Dr. Arthur Grollman at SUNY Stonybrook, we are examining DNA damage with the ultimate goal of relating specific lesions with biological activity. Specifically, we are focusing on mechanisms of chemical mutagenesis and the molecular biology of DNA repair. Dr. Grollman's group has established that a single zinc finger motif is involved in binding FPG protein to DNA duplexes with 8-oxodG. At CGL, I am involved with the modeling of the ZPG zinc-finger based on the NMR structure of XFIN. As in other zinc fingers, secondary structure consists of two antiparallel beta sheets, connected to a loop, connected to a helix. Tertiary structure is formed when two cysteines and two histidine residues of XFIN coordinate with zinc. Our model is constructed by substituting cysteines for the two histidine residues and replacing amino acids in the beta strands and alpha helix of XFIN with those found in a comparable region of FPG protein. Based on the primary structure, neither the type of helix (alpha helix, 310 helix, or a mixture of the two) nor the point where the helix originates is obvious. For example, the crystal structure of the zinc finger in GRE illustrates a different point for helix initiation than in XFIN. Therefore, we will use experimental methods to distinguish between several plausible models for the zinc finger structures. Following loop incorporation based of BLOOP from Fred Cohen's group at UCSF, we used molecular dynamics and mechanics to evaluate these models. C. Pabo. using combinatorial libraries, has recently shown the preferential patterns of helix side chains binding to DNA. We have used this data to further eliminate possible models. We utilized the program SCULPT by Mark Surles to modify our zinc finger structure. We are now beginning to use the program DOCK from UCSF to dock possible complexes. Lastly, Professor Grollman's laboratory is pursuing a site mutation study of the zinc finger to establish the importance of a key histidine residue.