PROPOSALS FOR THE ANGIOTENSIN-II RECEPTOR-BOUND CONFORMATION BY COMPARATIVE COMPUTER MODELING OF AII AND CYCLIC ANALOGS

A conformational search using high-temperature molecular dynamics on a ngiotensin II(AII) and on two cyclic S-S bridged analogs, namely [Hcy3 ,5]AII and [Cys3,5]AII, in conjunction with a cluster analysis based o n the similarities of the three-dimensional patterns of the binding an d activation elements, has led to putative AII receptor-bound conforma tions. These conformations are characterized by a compact folded shape of the peptide backbone, and by particular relative positions of the four pharmacophore groups, namely the aromatic moieties of the Tyr(4), His(6) and Phe(8) residues, and the C-terminal carboxyl group. This c ompact folded shape, arising from attractive electrostatic interaction s between the desolvated N- and C-terminal groups, is similar to the c rystallographically determined conformation of AII bound to the antibo dy Fab receptor. (C) Munksgaard 1995.