Role of Water in Mediating the Assembly of Alzheimer Amyloid-β Aβ16−22 Protofilaments

Abstract

The role of water in promoting the formation of protofilaments (the basic building blocks of amyloid fibrils) is investigated using fully atomic molecular dynamics simulations. Our model protofilament consists of two parallel β-sheets of Alzheimer Amyloid-β 16-22 peptides (Ac-K 16 -L 17 -V 18 -F 19 -F 20 -A 21 -E 22 -NH 2 ). Each sheet presents a distinct hydrophobic and hydrophilic face and together self-assemble to a stable protofilament with a core consisting of purely hydrophobic residues (L 17 ,F 19 ,A 21 ), with the two charged residues (K 16 , E 22 ) pointing to the solvent. Our simulations reveal a subtle interplay between a water mediated assembly and one driven by favorable energetic interactions between specific residues forming the interior of the protofilament. A dewetting transition, in which water expulsion precedes hydrophobic collapse, is observed for some, but not all molecular dynamics trajectories. In the trajectories in which no dewetting is observed, water expulsion and hydrophobic collapse occur simultaneously, with protofilament assembly driven by direct interactions between the hydrophobic side chains of the peptides (particularly between F-F residues). For those same trajectories, a small increase in the temperature of the simulation (on the order of 20 K) or a modest reduction in the peptide-water van der Waals attraction (on the order of 10%) is sufficient to induce a dewetting transition, suggesting that the existence of a dewetting transition in simulation might be sensitive to the details of the force field parametrization.

Hydrophobic interactions in the formation of secondary structures in small peptides

“…db's arise from empty spaces created by water exclusion between hydrophobic groups [37][38][39][40]42] and are the hallmark of interactions between nonpolar groups [33,34,[36][37][38][39][40][41][42][43] that are partially exposed to water. As such, db's are pertinent to the α-β transition in amyloidogenesis [26,27], which can be affected by pressure [27,[74][75][76]. Atomic PMF simulations indicated that temperature lowers both the cm and the db [34,37,38,42] whereas pressure raises them [77].…”

“…This indicates that, aside from protein core packing, hydrophobicity plays an important role in the conformation of small peptides. Understanding this role is useful, for example, to account for the emergence of enhanced β structures in proteins implicated in amyloid and prion diseases [25][26][27].…”

Dynamics of locking of peptides onto growing amyloid fibrils

“…These observations show that dehydration, resulting in the formation of the dry zipper region (4) as the monomer locks into the fibril lattice, is a key event in the growth of the amyloid fibrils. We surmise that interactions involving water must play an important role in the rate of fibril growth (41,42).…”

Replica exchange molecular dynamics of the thermodynamics of fibril growth of Alzheimer's Aβ42 peptide

“…21 The growth process has also been probed by various computational studies that study how monomers of Aβ-fragments add to preformed oligomers. [22][23][24][25][26][27] For instance, Buchete and Hummer 28 proposed from all-atom molecular dynamics simulations of Aβ 40 a three-step process, where strong hydrophobic interactions align the C-terminal segments of the incoming peptide with such in the fibril encoura) Electronic mail: minghan2000@gmail.com. b) Electronic mail: hansmann@mtu.edu.…”