A molecular dynamics study of the early stages of amyloid‐β(1–42) oligomerization: The role of lipid membranes

Abstract

As research progresses towards understanding the role of the amyloid-β (Aβ) in Alzheimer’s disease, certain aspects of the aggregation process for Aβ are still not clear. In particular, the accepted constitution of toxic aggregates in neurons has shifted towards small oligomers. However, the process of forming these oligomers in cells is still not fully clear. Even more interestingly, it has been implied that cell membranes, and, in particular, anionic lipids within those membranes, play a key role in the progression of Aβ aggregation, but the exact nature of the Aβ-membrane interaction in this process is still unknown. In this work, we use a thermodynamic cycle and umbrella sampling molecular dynamics to investigate dimerization of the 42-residue Aβ peptide on model zwitterionic dipalmitoylphosphatidylcholine (DPPC) or model anionic dioleoylphosphatidylserine (DOPS) bilayer surfaces. We determined that Aβ dimerization was strongly favored through interactions with the DOPS bilayer. Further, our calculations showed that the DOPS bilayer promoted strong protein-protein interactions within the Aβ dimer, while DPPC favored strong protein-lipid interactions. By promoting dimer formation and subsequent dimer release into the solvent, the DOPS bilayer acts as a catalyst in Aβ aggregation through converting Aβ monomers in solution into Aβ dimers in solution without substantial a free energy cost.

Maximally asymmetric transbilayer distribution of anionic lipids alters the structure and interaction with lipids of an amyloidogenic protein dimer bound to the membrane surface

“…Previous studies have also suggested the importance of anionic lipids on the surface in promoting beta-amyloid binding, folding, and aggregation (Wong et al, 2009; Davis and Berkowitz, 2010; Yu et al, 2013). Our preliminary study of D42 binding to lipid surface containing PS revealed a similar, but slightly stronger, domain aggregation effect than the ordered PC surface (results not shown).…”

“…Electrostatic interactions between the charged residues of the protein and lipid polar headgroups have been proposed to drive the initial membrane surface binding of beta-sheet rich beta-amyloid oligomers in various bilayer systems (Davis and Berkowitz, 2010; Jang et al, 2013; Yu et al, 2013; Tofoleanu et al, 2015). Those studies investigated single- and multiple-component lipid bilayers consisting of PC, PS, phosphatidylethanolamine (PE), and phosphatidylglycerol (PG) of different acyl chain compositions.…”

Amyloid β Protein and Alzheimer’s Disease: When Computer Simulations Complement Experimental Studies

“…Davis and Berkowitz have used REMD simulations and umbrella sampling to study the adsorption of Aβ1-42 on bilayers (283,284) and possible mechanisms of dimerization, focusing in particular on the role of electrostatic interactions. (285) They found that lipid-protein interactions dominate the behaviour of Aβ on dipalmitoyl-phosphatidylcholine (DPPC) bilayers, whereas protein-protein interactions prevail on negatively charged 2-dioleoyl-sn-glycero-3-phospho-l-serine (DOPS) bilayers. Independent simulation studies arrived at the conclusion that the adsorption of Aβ on membranes follows a two-step mechanism.…”

Scaling and alpha-helix regulation of protein relaxation in a lipid bilayer

“…[24][25][26][27][28][29] Simulation of aggregation and release processes 26,30,31 are particularly relevant to the work presented here because they can compete with unfolding, penetration, and binding phenomena.…”