Islet amyloid polypeptide, IAPP or amylin, is a 37-residue peptide hormone coexpressed with insulin by pancreatic beta-cells. The aggregation of human IAPP (hIAPP) into amyloid deposits is associated with type II diabetes. Substantial evidence suggests that the interaction of anionic membranes with hIAPP may facilitate peptide aggregation and the N-terminal 1-19 fragment (IAPP(1-19)) plays an important role in peptidemembrane interaction. As a first step to understand how structural differences between human and rat IAPP peptides in membranes may influence the later oligomerization process, we have investigated the structures and orientations of hIAPP(1-19) and the less toxic rIAPP(1-19) (i.e., the H18R mutant of hIAPP(1-19)) monomers in anionic POPG bilayers by performing replica exchange molecular dynamics (REMD) simulations. On the basis of similar to 20 mu s REMD simulations started from a random coil conformation of the peptide placed in water, we find that unfolded h(r)IAPP(1-19) can insert into the bilayers and the membrane-bound peptide stays mainly at the lipid head-tail interface. hIAPP(1-19) displays higher helix propensity than rIAPP(1-19), especially in the L12-L16 region. The helix is oriented parallel to the bilayer surface and buried in the membrane 0.3-0.8 nm below the phosphorus atoms, consistent with previous electron paramagnetic resonance data. The helical conformation is an amphiphilic helix with its hydrophilic and hydrophobic faces pointing, respectively, to the lipid head and tail regions. The H18R substitution enhances the electrostatic interactions of IAPP(1-19) with the membrane, while it weakens the intrapeptide interactions crucial for helix formation, thus leading to lower helix propensity of rIAPP(1-19). Implications of our simulation results on the membrane-mediated IAPP(1-19) oligomerization are discussed.