Acidic Sphingomyelinase Interactions with Lysosomal Membranes and Cation Amphiphilic Drugs: a Molecular Dynamics Investigation DOI Creative Commons
Simone Scrima, Matteo Lambrughi, Kenji Maeda

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 14, 2023

Abstract Lysosomes are pivotal in cellular functions and disease, influencing cancer progression therapy resistance with Acid Sphingomyelinase (ASM) governing their membrane integrity. Moreover, cation amphiphilic drugs (CADs) known as ASM inhibitors have anti-cancer activity, but the structural mechanisms of interactions lysosomal poorly explored. Our study, leveraging all-atom explicit solvent molecular dynamics simulations, delves into interaction glycosylated effects one CAD representatives, i.e., ebastine on ASM. results confirm association to through saposin domain, previously only showed coarse grained models. Furthermore, we elucidated role specific residues ASM-induced curvature lipid recruitment orientation. Ebastine also interferes at level a loop catalytic domain engaging interactions. computational approach, applicable various CADs or compositions, provides insights membrane, offering valuable tool for future studies.

Language: Английский

Acidic sphingomyelinase interactions with lysosomal membranes and cation amphiphilic drugs: A molecular dynamics investigation DOI Creative Commons
Simone Scrima, Matteo Lambrughi, Lorenzo Favaro

et al.

Computational and Structural Biotechnology Journal, Journal Year: 2024, Volume and Issue: 23, P. 2516 - 2533

Published: June 2, 2024

Lysosomes are pivotal in cellular functions and disease, influencing cancer progression therapy resistance with Acid Sphingomyelinase (ASM) governing their membrane integrity. Moreover, cation amphiphilic drugs (CADs) known as ASM inhibitors have anti-cancer activity, but the structural mechanisms of interactions lysosomal poorly explored. Our study, leveraging all-atom explicit solvent molecular dynamics simulations, delves into interaction glycosylated effects CAD representatives, i.e., ebastine, hydroxyebastine loratadine, on ASM. results confirm association to through saposin domain, previously only shown coarse-grained models. Furthermore, we elucidated role specific residues ASM-induced curvature lipid recruitment orientation. CADs also interfere at level a loop catalytic domain engaging interactions. computational approach, applicable various or compositions, provides insights membrane, offering valuable tool for future studies.

Language: Английский

Citations

0
Acidic Sphingomyelinase Interactions with Lysosomal Membranes and Cation Amphiphilic Drugs: a Molecular Dynamics Investigation DOI Creative Commons
Simone Scrima, Matteo Lambrughi, Kenji Maeda

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 14, 2023

Abstract Lysosomes are pivotal in cellular functions and disease, influencing cancer progression therapy resistance with Acid Sphingomyelinase (ASM) governing their membrane integrity. Moreover, cation amphiphilic drugs (CADs) known as ASM inhibitors have anti-cancer activity, but the structural mechanisms of interactions lysosomal poorly explored. Our study, leveraging all-atom explicit solvent molecular dynamics simulations, delves into interaction glycosylated effects one CAD representatives, i.e., ebastine on ASM. results confirm association to through saposin domain, previously only showed coarse grained models. Furthermore, we elucidated role specific residues ASM-induced curvature lipid recruitment orientation. Ebastine also interferes at level a loop catalytic domain engaging interactions. computational approach, applicable various CADs or compositions, provides insights membrane, offering valuable tool for future studies.

Language: Английский

Citations

0