Aspartate-bond isomerization affects the major conformations of synthetic peptides

The aspartic acid bond changes to an \u3b2-aspartate bond frequently as a side-reaction during peptide synthesis and often as a post-translational modification of proteins. The formation of \u3b2-aspartate bonds is reported to play a major role not only in protein metabolism, activation and deactivation, but also in pathological processes such as deposition of the neuritic plaques of Alzheimer's disease. Recently, we reported how conformational changes following the aspartic-acid-bond isomerization may help the selective aggregation and retention of the amyloid \u3b2 peptide in affected brains (Fabian et al., 1994). In the current study we used circular dichroism, Fourier-transform infrared spectroscopy, and molecular modeling to characterize the general effect of the \u3b2 aspartate-bond formation on the conformation of five sets of synthetic model peptides. Each of the non-modified, parent peptides has one of the major secondary structures as the dominant spectro-scopically determined conformation: a type I \u3b2 turn, a type II \u3b2 turn, short segments of \u3b1 or 310 helices, or extended \u3b2 strands. We found that both types of turn structures are stabilized by the aspartic acid-bond isomerization. The isomerization at a terminal position did not affect the helix propensity, but placing it in mid-chain broke both the helix and the \u3b2-pleated sheet with the formation of reverse turns. The alteration of the geometry of the lowest energy reverse turn was also supported by molecular dynamics calculations. The tendency of the aspartic acid-bond isomerization to stabilize turns is very similar to the effect of incorporating sugars into synthetic peptides and suggests a common feature of these post-translational modifications in defining the secondary structure of protein fragments.Peer reviewed: YesNRC publication: Ye