ASPARTATE-BOND ISOMERIZATION AFFECTS THE MAJOR CONFORMATIONS OF SYNTHETIC PEPTIDES

The aspartic acid bond changes to an beta-aspartate bond frequently as a side-reaction during peptide synthesis and often as a post-translat ional modification of proteins. The formation of beta-aspartate bonds is reported to play a major role not only in protein metabolism, activ ation and deactivation, but also in pathological processes such as dep osition of the neuritic plaques of Alzheimer's disease. Recently, we r eported how conformational changes following the aspartic-acid-bond is omerization may help the selective aggregation and retention of the am yloid beta peptide in affected brains (Fabian et al., 1994). In the cu rrent study we used circular dichroism, Fourier-transform infrared spe ctroscopy, and molecular modeling to characterize the general effect o f the beta-aspartate-bond formation on the conformation of five sets o f synthetic model peptides. Each of the non-modified, parent peptides has one of the major secondary structures as the dominant spectroscopi cally determined conformation: a type I beta turn, a type II beta turn , short segments of alpha or 3(10) helices, or extended beta strands. We found that both types of turn structures are stabilized by the aspa rtic acid-bond isomerization. The isomerization at a terminal position did not affect the helix propensity, but placing it in mid-chain brok e both the helix and the beta-pleated sheet with the formation of reve rse turns. The alteration of the geometry of the lowest energy reverse turn was also supported by molecular dynamics calculations. The tende ncy 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 modificatio ns in defining the secondary structure of protein fragments.