Abstract

Alzheimer’s disease is associated with aggregates of amyloid-β (Aβ) peptides. Aβ peptides exist in extracellular fluids, whose fluidity is higher than that of intracellular environments, suggesting that flow effects should be considered in the aggregation process. Recently, it was experimentally reported that flow on extracellular membrane surfaces enhances the aggregation of Aβ peptides. However, the molecular mechanism underlying this phenomenon remains unclear.

To investigate this problem, we developed a new nonequilibrium molecular dynamics (NEMD) simulation method suitable for generating flow on biological membrane surfaces [1]. In this method, the centre of mass of the lipid bilayer is constrained using Lagrange multipliers to prevent drift of lipid molecules, while external lateral forces are applied to water molecules to induce flow. In addition, the temperature of the system is controlled using the Nosé–Hoover thermostat.

Application of this method to membrane–water systems successfully reproduced parabolic velocity profiles similar to Poiseuille flow, as shown in Fig. 1. Using this approach, we further performed NEMD simulations of systems containing multiple amyloid-β fragments on membrane surfaces and investigated their aggregation processes under flow conditions. The simulations revealed that peptide aggregation is enhanced in the presence of flow compared with quiescent conditions. We will also discuss the molecular mechanism by which flow promotes peptide aggregation.

Figure 1 –Poiseuille-like flow generated between lipid bilayers.

References

[1] M. Otawa, S. G. Itoh, and H. Okumura, J. Chem. Theory Comput. 20, 10199 (2024).