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Acidic sphingomyelinase interactions with lysosomal membranes and cation amphiphilic drugs: A molecular dynamics
Simone Scrima1,2, Matteo Lambrughi1, Lorenzo Favaro1
1Cancer Structural Biology, Center for Autophagy, Recycling and Disease, Danish Cancer Institute, Copenhagen 2100, Denmark.
Abstract:
Lysosomes are pivotal in cellular functions and disease, influencing cancer progression and therapy resistance with Acid Sphingomyelinase (ASM) governing their membrane integrity. Moreover, cation amphiphilic drugs (CADs) are known as ASM inhibitors and have anti-cancer activity, but the structural mechanisms of their interactions with the lysosomal membrane and ASM are poorly explored. Our study, leveraging all-atom explicit solvent molecular dynamics simulations, delves into the interaction of glycosylated ASM with the lysosomal membrane and the effects of CAD representatives, i.e., ebastine, hydroxyebastine and loratadine, on the membrane and ASM. Our results confirm the ASM association to the membrane through the saposin domain, previously only shown with coarse-grained models. Furthermore, we elucidated the role of specific residues and ASM-induced membrane curvature in lipid recruitment and orientation. CADs also interfere with the association of ASM with the membrane at the level of a loop in the catalytic domain engaging in membrane interactions. Our computational approach, applicable to various CADs or membrane compositions, provides insights into ASM and CAD interaction with the membrane, offering a valuable tool for future studies.
Insights
This study reveals how Acid Sphingomyelinase (ASM) binds to lysosomal membranes and how drugs (CADs) disrupt this interaction, offering insights into cancer therapy mechanisms.
Area of Science:
- Cell Biology
- Biochemistry
- Computational Biophysics
Background:
- Lysosomes are crucial for cellular functions and disease, with Acid Sphingomyelinase (ASM) regulating membrane integrity.
- Cation amphiphilic drugs (CADs) inhibit ASM and show anti-cancer effects, but their interaction mechanisms are unclear.
Purpose of the Study:
- To investigate the structural interactions of glycosylated ASM with the lysosomal membrane.
- To explore the effects of CADs (ebastine, hydroxyebastine, loratadine) on ASM and membrane dynamics.
Main Methods:
- All-atom explicit solvent molecular dynamics simulations were employed.
- Investigated glycosylated ASM association with the lysosomal membrane.
- Analyzed the impact of specific CADs on ASM-membrane interactions.
Main Results:
- Confirmed ASM membrane association via the saposin domain, elucidating residue roles and membrane curvature effects.
- Demonstrated CADs interfere with ASM-membrane binding by interacting with a catalytic domain loop.
- Provided a computational framework applicable to diverse CADs and membrane compositions.
Conclusions:
- The study elucidates the molecular mechanisms of ASM-lysosomal membrane association and CAD interference.
- Offers a valuable computational tool for future research on ASM, CADs, and lysosomal membrane dynamics.
- Provides foundational insights for developing novel anti-cancer therapies targeting ASM.
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