Abstract
The Amyloid-β (Aβ)-derived, sphingolipid binding domain (SBD) peptide is a fluorescently tagged probe used to trace the diffusion behavior of sphingolipid-containing microdomains in cell membranes through binding to a constellation of glycosphingolipids, sphingomyelin, and cholesterol. However, the molecular details of the binding mechanism between SBD and plasma membrane domains remain unclear. Here, to investigate how the peptide recognizes the lipid surface at an atomically detailed level, SBD peptides in the environment of raft-like bilayers were examined in micro-seconds-long molecular dynamics simulations. We found that SBD adopted a coil-helix-coil structural motif, which binds to multiple GT1b gangliosides via salt bridges and CH–π interactions. Our simulation results demonstrate that the CH–π and electrostatic forces between SBD monomers and GT1b gangliosides clusters are the main driving forces in the binding process. The presence of the fluorescent dye and linker molecules do not change the binding mechanism of SBD probes with gangliosides, which involves the helix-turn-helix structural motif that was suggested to constitute a glycolipid binding domain common to some sphingolipid interacting proteins, including HIV gp120, prion, and Aβ.
Highlights
Sphingolipid-containing microdomains in cellular plasma membrane play important roles in signaling, endocytic, and secretory pathways [1,2]
In this study we applied extensive molecular dynamics (MD) simulations to explore the detailed mechanism of the sphingolipid binding domain (SBD)–GT1b interaction with three questions in mind: (i) How do SBD monomers interact with the preferred ganglioside, GT1b, in the membrane? (ii) What are the key amino acids mediating the binding? (iii) Do fluorescent dye and linker molecules influence the gangliosides binding configurations of SBD probe? Such a mechanistic study is beneficial for the future design of novel sphingolipid and microdomain tracers, and for understanding the recognizing mechanisms of pathogen invasion into cells
SBD peptide was suggested to bind to gangliosides in the presence of sphingomyelin and cholesterol using surface plasmon resonance and fluorescence correlation spectroscopic assays [37,38]
Summary
Sphingolipid-containing microdomains in cellular plasma membrane play important roles in signaling, endocytic, and secretory pathways [1,2]. Glycosphingolipids (GSLs) constitute a large and diverse class of lipids with carbohydrate-containing head groups These complicated lipids are important mediators of pathogen infection [3,4], providing a platform for bacteria [5,6], virus [7], and toxins [8] to enter the host cells. The molecular interactions between SBD and poly-sialic gangliosides, such as GT1b, remain unclear. Such interactions may mediate membrane domain-specific recognition and characteristic diffusion. In this study we applied extensive molecular dynamics (MD) simulations to explore the detailed mechanism of the SBD–GT1b interaction with three questions in mind: (i) How do SBD monomers interact with the preferred ganglioside, GT1b, in the membrane? In this study we applied extensive molecular dynamics (MD) simulations to explore the detailed mechanism of the SBD–GT1b interaction with three questions in mind: (i) How do SBD monomers interact with the preferred ganglioside, GT1b, in the membrane? (ii) What are the key amino acids mediating the binding? (iii) Do fluorescent dye and linker molecules influence the gangliosides binding configurations of SBD probe? Such a mechanistic study is beneficial for the future design of novel sphingolipid and microdomain tracers, and for understanding the recognizing mechanisms of pathogen invasion into cells
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