The Structure of Intrinsically Disordered Peptides Implicated in Amyloid Diseases: Insights from Fully Atomistic Simulations - Computational Modeling of Biological Systems - page 220

Indeed, our simulations showed that although the E22Q mutant did not affect the
bend structure in the A“ E22Q mutant, it weakened the interactions between the
CHC and the bend, leading to an increased population of “-structure in the CHC.
Our free energy analysis further indicated that the E22Q mutation increases A“
aggregation rates by lowering the barrier for A“ monomer deposition onto a fibril.

3.3 Effect of Solution Conditions on A “ Structure

Whereas on average A“42 peptide adopts disordered coil-turn rich structure in
aqueous solution, it adopts an ordered helix-rich conformation in apolar solvents
[ 59 , 60 ]. In mixed solvent of hexafluoroisopropanol (HFIP) and water with 80:20
ratio in volume, NMR studies [ 59 ] showed it adopts a helix-turn-helix structure,
with two helices nearly at a right angle (helix 1: residues 7-27; helix 2: residues
28-39). To understand the solvent effect, simulations with explicit solvent models
were used to study the conformational preference of A“(1-42) in different solvents
[ 61 - 63 ]. The simulations revealed new insights into the conformations populated by
the A“ peptide in nonaqueous solvents, and showed that the apolar solvents HFIP
(hexafluoroisopropanol) and TFE (2,2,2-trifluoro-ethanol) promote helix formation,
that the polar solvent DMSO (dimethyl sulfoxide) causes the unfolding of the
C-terminal part, and that the polar solvent water induces the '-helix to “-sheet
transition for the C-terminal part. These simulations may explain why A“42
aggregation generally occurs out of apolar membrane and in extracellular water
environment, where A“42 is converted from nonaggregating helical conformation
to aggregation prone coil and sheet-rich conformations.

4 The IAPP Peptide

Type II diabetes is an age and life-style related disease involving insulin resistance
and loss of “-cell mass. A hallmark of this disease is the presence of amyloid fibrils
of the Islet Amyloid IAPP peptide (also known as amylin) in the “-cells of the
pancreas [ 22 ]. The IAPP is a 37-residue peptidic by-product of a larger precursor
protein, and it is co-secreted along with insulin by the pancreatic islet “-cells. Under
pathological conditions, IAPP is over-expressed and aggregates. As in the case
of the A“ peptide implicated in AD, both early oligomers and mature fibrils of
IAPP appear to be toxic. The IAPP peptide is present in many mammalian species,
including rodents. Although the rat and human IAPP forms (Fig. 3 ) differ only by
six amino acids, only the human form aggregates. Transgenic rodents (rodents with
a human form of IAPP) on a high fat diet can develop type II diabetes with the
accompanying aggregation of the IAPP peptide [ 64 ].
The structures of the human and the rat forms of IAPP monomers were studied
independently using REMD by Wu et al. [ 65 ] using an implicit solvent (igb5) is the