The Structure of Intrinsically Disordered Peptides Implicated in Amyloid Diseases: Insights from Fully Atomistic Simulations - Computational Modeling of Biological Systems - page 221

Fig. 3 Primary sequences of human and rat IAPP. The sequence differences between rat IAPP and
human IAPP are underlined . The segment in which these mutational differences occur is shown in
the red box
Amber force field ff96 and by Reddy et al. [ 66 , 67 ] using an explicit solvent and
the Gromos96 53a6 force field. The aim of these simulations was twofold: (1) to
obtain structural information about the monomeric states of these peptides that is not
available from experiments and (2) to explore whether conformational differences
were present in the monomeric form that could explain why the human variant of
IAPP aggregated and the rodent form did not. The results of the simulations by
the two groups are in remarkable agreement. Representative aggregation prone and
nonaggregation prone structures of the human from simulation are shown in Fig. 4 .
The nonaggregation prone conformations of human IAPP are very similar to those
of rat IAPP.
The rat form populates predominantly helix-coil structures, with helicity present
in the N-terminal region. The simulation results are in good agreement with NMR
studies [ 68 , 69 ] that point to helicity in this region, and with result from the AGADIR
program [ 70 ] that suggest that the N-terminal region has high helical propensity. The
human form, on the other hand, coexists between helix-coil structures, helix-sheet
structures, and “-hairpin structures. The human and rat forms share the same N-
terminal region, and NMR studies on the human form show that, as in the rat case,
there is helical propensity in this region [ 69 , 71 ]. The presence of “-rich elements is
supported by 2D-IR experiments [ 72 ] as well as by ion-mobility mass spectrometry
(IMMS) studies from the Bowers group [ 65 ]. IMMS generates collision-cross
sections, a measure of the overall size of the ions under study. The IMMS spectra
for the human form differed from the rat form by the presence of an extended
feature. Calculation of theoretical cross sections showed that the compact structures
seen in experiment were consistent with the helix-coil structures seen in simulation,
while the extended feature was consistent with a “-hairpin structure. The simulations
suggest that the “-rich hairpin conformation may be a direct precursor to aggregation
[ 65 ](Fig. 4 ). The idea that human IAPP possesses both aggregation prone and
nonaggregation prone conformations is supported by earlier CD experiments by the
Kayed group [ 73 ].