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Phosphatidylserine Exposed Lipid Bilayer Models for Understanding Cancer Cell Selectivity of Natural Compounds: A Molecular Dynamics Simulation Study.

ABSTRACT: Development of drugs that are selectively toxic to cancer cells and safe to normal cells is crucial in cancer treatment. Evaluation of membrane permeability is a key metric for successful drug development. In this study, we have used in silico molecular models of lipid bilayers to explore the effect of phosphatidylserine (PS) exposure in cancer cells on membrane permeation of natural compounds Withaferin A (Wi-A), Withanone (Wi-N), Caffeic Acid Phenethyl Ester (CAPE) and Artepillin C (ARC). Molecular dynamics simulations were performed to compute permeability coefficients. The results indicated that the exposure of PS in cancer cell membranes facilitated the permeation of Wi-A, Wi-N and CAPE through a cancer cell membrane when compared to a normal cell membrane. In the case of ARC, PS exposure did not have a notable influence on its permeability coefficient. The presented data demonstrated the potential of PS exposure-based models for studying cancer cell selectivity of drugs.

SUBMITTER: Radhakrishnan N

PROVIDER: S-EPMC8780679 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Phosphatidylserine Exposed Lipid Bilayer Models for Understanding Cancer Cell Selectivity of Natural Compounds: A Molecular Dynamics Simulation Study.

Radhakrishnan Navaneethan N Kaul Sunil C SC Wadhwa Renu R Sundar Durai D

Membranes 20220101 1

Development of drugs that are selectively toxic to cancer cells and safe to normal cells is crucial in cancer treatment. Evaluation of membrane permeability is a key metric for successful drug development. In this study, we have used in silico molecular models of lipid bilayers to explore the effect of phosphatidylserine (PS) exposure in cancer cells on membrane permeation of natural compounds Withaferin A (Wi-A), Withanone (Wi-N), Caffeic Acid Phenethyl Ester (CAPE) and Artepillin C (ARC). Mole ...[more]

PMID: 35054590

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Project description:Transient receptor potential vanilloid subtype 1 (TRPV1) is a heat-sensitive ion channel also involved in pain sensation, and is the receptor for capsaicin, the active ingredient of hot chili peppers. The recent structures of TRPV1 revealed putative ligand density within the S1 to S4 voltage-sensor-like domain of the protein. However, questions remain regarding the dynamic role of the lipid bilayer in ligand binding to TRPV1. Molecular dynamics simulations were used to explore behavior of capsaicin in a 1-palmitoyl-2-oleoyl phosphatidylcholine bilayer and with the target S1-S4 transmembrane helices of TRPV1. Equilibrium simulations reveal a preferred interfacial localization for capsaicin. We also observed a capsaicin molecule flipping from the extracellular to the intracellular leaflet, and subsequently able to access the intracellular TRPV1 binding site. Calculation of the potential of mean force (i.e., free energy profile) of capsaicin along the bilayer normal confirms that it prefers an interfacial localization. The free energy profile indicates that there is a nontrivial but surmountable barrier to the flipping of capsaicin between opposing leaflets of the bilayer. Molecular dynamics of the S1-S4 transmembrane helices of the TRPV1 in a lipid bilayer confirm that Y511, known to be crucial to capsaicin binding, has a distribution along the bilayer normal similar to that of the aromatic group of capsaicin. Simulations were conducted of the TRPV1 S1-S4 transmembrane helices in the presence of capsaicin placed in the aqueous phase, in the lipid, or docked to the protein. No stable interaction between ligand and protein was seen for simulations initiated with capsaicin in the bilayer. However, interactions were seen between TRPV1 and capsaicin starting from the cytosolic aqueous phase, and capsaicin remained stable in the majority of simulations from the docked pose. We discuss the significance of capsaicin flipping from the extracellular to the intracellular leaflet and mechanisms of binding site access by capsaicin.

Dataset Information

Phosphatidylserine Exposed Lipid Bilayer Models for Understanding Cancer Cell Selectivity of Natural Compounds: A Molecular Dynamics Simulation Study.

Publications

Phosphatidylserine Exposed Lipid Bilayer Models for Understanding Cancer Cell Selectivity of Natural Compounds: A Molecular Dynamics Simulation Study.

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