STRUCTURE AND COMPARISON OF HIV-1 GP120 PEPTIDES IN COMPLEX WITH HIV-1 NEUTRALIZING FABS. R. L. Stanfield, J. B. Ghiara, J. M. Rini, E. A. Stura, A. C. Satterthwait, I. A. Wilson, The Scripps Research Institute, 10666 N. Torrey Pines Road, La Jolla, CA 92037

Crystal structures have been determined for three different HIV-1 neutralizing antibody Fab fragments in complex with several linear and cyclic peptides. The Fabs were all raised against the same 40-amino acid disulfide linked peptide, corresponding in sequence to the principal neutralizing determinant (PND) loop from HIV-1 gp120 (MN isolate). The complexes studied include Fab 50.1 (MN specific) with linear peptide, Fab 59.1 (broadly specific) with two linear peptides, and Fab 58.2 (potent and broadly specific) in complex with one linear and three cyclic peptides. The three different antibodies recognize overlapping epitopes on the PND loop (50.1-CKRIHIGPG, 59.1-HIGPGRAFYT, 58.2-RIHIGPGRAFY). The peptides bound to 50.1 and 59.1 are very similar, but differ from peptides bound to 58.2 around the GPGR region. Information from the early Fab- peptide complex structures has been used in the design of constrained peptides. These peptides have an Aib (a-aminoisobutyric acid) residue in the place of an Ala residue involved in a helical turn. The Aib containing peptides all bind to Fab 58.2 more tightly than their non-Aib containing counterparts, and unpublished NMR work has shown that the Aib residue confers additional structure on the peptides in solution. The addition of the Aib residue to the peptides does not significantly change their conformation while bound to Fab. The structures for the peptides as bound to the different Fabs will be compared and contrasted.