Effects of lipids on the activity and structural dynamics of gamma secretase: A study using coarse-grained molecular dynamics simulations

Gamma secretase(GS)is an intramembranous enzyme that acts on the amyloid precursor protein and Notch inside lipid membranes.The enzyme is responsible for amyloid-β propagation,one of the well-known causes of Alzheimer’s disease.However,the effects of lipids on GS activity and structural dynamics are unknown.Therefore,in this study,we performed coarse-grained molecular dynamics simulations to probe the effects of five individual lipids on GS.These lipids included 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine(POPE),1-palmitoyl2-oleoyl-sn-glycero-3-phosphocholine(POPC),1,2-dipalmitoyl-sn-phosphatidylcholine(DOPC),2-dimyristoyl-snglycero-3-phosphocholine(DMPC),and 1,2-dilauroyl-sn-glycero-3-phosphocholine(DLPC).These lipids are structurally characterized by different heads(i.e.,NH_(3)[PE]for POPE vs.NC_(3)[PC]for POPC),number of double bonds(one for POPC vs.two for DOPC),and alkyl tail chain lengths(16:1/18:1 for DOPC vs.14:0/14:0 for DMPC vs.12:0/12:0 for DLPC).This indicates distinct microenvironments and adjustable structural elements for catalytic function when GS is embedded.Our results revealed that the presence of more unsaturated bonds in DOPC than in POPC resulted in greater GS stability.Moreover,lipids with short alkyl tail chains or with PC heads instead of PE heads had improved mobility of the sixth transmembrane helix of GS,which is responsible for the considerable active site flexibility and presenilin 1 subunit plasticity.The length of the DMPC alkyl tail chain was between that of DOPC and DLPC because the up-down and cross-correlation motions of GS in DMPC was the lowest among the three lipids,and GS mobility in DMPC was the lowest among all five lipids.This may be because the alkyl tail chain length(i.e.,3.8 nm thickness of the DMPC bilayer)was suitable for GS embedding,thereby restraining more GS motions than that of the long(DOPC)or short lipids(DLPC).Collectively,these results indicated that GS activity can be modulated through changes in conformational fluctuations,structural perturbations,molecular motion,and cross-correlation motion when embedded in different lipids.Exploration of such fundamental information can reveal the possible mechanisms by which GS is affected by individual lipid species.

Molecular mechanisms of direct and indirect interplay between amyloid𝛽β42 oligomer and characteristic lipids

Accumulating evidence suggests that toxicity in patients with Alzheimer’s disease originates from the deposition of Aβ42 aggregates on the neuronal cell membrane.However,the molecular mechanism underlying Aβ42 aggrega-tion on the surface of different lipids is poorly understood.In this study,coarse-grained and all-atomic molecular dynamics(MD)simulations were used to characterize the assembly process of two Aβ42 pentameric oligomers and the perturbation“footprints”of three characteristic lipid constitute bilayer membranes:POPC,POPG,and their hybrid PcPg composed of POPG and POPC in a 1:3 ratio.Our results revealed that the Aβ decamer was first formed in the water phase prior to its contact with the lipid surface,indicating that the water phase plays an incubation role in Aβ42 oligomer aggregation.Moreover,the presence of any of the three lipids accelerated the assembly process of the two Aβ42 pentameric.The aggregation rate and aggregate conformation were strictly dependent on lipid charge,oligomer size,and degree of aggregation.In turn,the presence of oligomer impacted the surface of the lipid,generating a clear perturbation“footprint”,regardless of whether the interplay was direct or indirect,revealing for the first time that the indirect interaction is not seamless and can be detected clearly at the molecular level.Indirect interplay stands for the non-contacting interaction interfaced by the water phase,indicating a metastable state with long-range interaction under non-shaking conditions.Our results reveal the crucial role of non-contacting interactions in determining the phase status of zwitterionic membranes.