Edited by Harold A. Scheraga, Cornell University, Ithaca, NY, and approved August 27, 2004 (received for review June 25, 2004)
We use long multiple trajectories generated by molecular dynamics simulations to probe the stability of oligomers of Aβ16–22 (KLVFFAE) peptides in aqueous urea solution. High concentration of urea promotes the formation of β-strand structures in Aβ16–22 monomers, whereas in water they adopt largely compact random coil structures. The tripeptide system, which forms stable antiparallel β-sheet structure in water, is destabilized in urea solution. The enhancement of β-strand content in the monomers and the disruption of oligomeric structure occur largely by direct interaction of urea with the peptide backbone. Our simulations suggest that the oligomer unbinding dynamics is determined by two opposing effects, namely, by the increased propensity of monomers to form β-strands and the rapid disruption of the oligomers. The qualitative conclusions are affirmed by using two urea models. Because the proposed destabilization mechanism depends largely on hydrogen bond formation between urea and the peptide backbone, we predict that high urea concentration will destabilize oligomers of other amyloidogenic peptides as well.
↵ † To whom correspondence may be addressed. E-mail: thirum{at}glue.umd.edu or dklimov{at}gmu.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: Aβ, amyloid β; MD, molecular dynamics; OPLS, optimized potentials for liquid simulations; WS, Weerasinghe and Smith; RC, random coil; ASA, accessible surface area; HB, hydrogen bond; FSS, first solvation shell; DO, disordered oligomers; OO, ordered oligomers.
