Free-Energy and Position-Dependent Diffusion Profiles Shape Passive Permeation of a Semisynthetic Naphthoquinone across a Model Lipid Bilayer.
- 1Faculty of Pharmaceutical Sciences, Federal University of Amazonas, Manaus, Amazonas69080-900, Brazil.
- 2Center for Innovation in Artificial Intelligence for Health (CIIA - Saúde/UFMG), Belo Horizonte, Minas Gerais31270-901, Brazil.
Abstract
Passive membrane permeation depends on both solute partitioning and coordinate-dependent mobility, but their separate and spatial-coupling contributions are rarely quantified within a common resistance framework. CNFD (6b,7-dihydro-5H-cyclopenta[b]naphtho[2,1-d]furan-5,6(9aH)-dione), a semisynthetic naphthoquinone with low-micromolar cytotoxicity and tumor-growth inhibition in preclinical models, was examined in a four-component model lipid bilayer. Established simulated tempering-enhanced umbrella sampling, WHAM, the Hummer positional-autocorrelation formalism, and the inhomogeneous solubility-diffusion model were combined. Three independent replicas yielded favorable interfacial partitioning (-4.66 kJ mol-1) and a positive membrane-center free energy (+12.36 kJ mol-1). Controlled profile substitutions showed that PMF heterogeneity and position-dependent diffusion amplified CNFD resistance by factors of 10.54 and 14.89, respectively, whereas their residual spatial-coupling factor was 1.134. The PMF maximum and diffusion minimum were separated by 2.14 nm. The primary intrinsic Peff was 9.09 × 10-2 cm s-1. Applying the same analysis to β-lapachone and plumbagin identified contrasting resistance regimes, with plumbagin combining a favorable center PMF with much lower central resistance localization. These results show how spatially separated free-energy and mobility landscapes govern intrinsic lipid-phase permeation.
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BibTeX
@article{ferreira2026freeenergy,
title = {{Free-Energy and Position-Dependent Diffusion Profiles Shape Passive Permeation of a Semisynthetic Naphthoquinone across a Model Lipid Bilayer.}},
author = {Fábio J N Ferreira and Tallita Marques Machado and Fernanda Guilhon-Simplicio},
journal = {The journal of physical chemistry. B},
year = {2026},
month = sep,
doi = {10.1021/acs.jpcb.6c02574},
url = {https://europepmc.org/article/MED/42915338},
note = {CC BY},
}
RIS
TY - JOUR
TI - Free-Energy and Position-Dependent Diffusion Profiles Shape Passive Permeation of a Semisynthetic Naphthoquinone across a Model Lipid Bilayer.
AU - Fábio J N Ferreira
AU - Tallita Marques Machado
AU - Fernanda Guilhon-Simplicio
PY - 2026
DA - 2026/09/01
JO - The journal of physical chemistry. B
DO - 10.1021/acs.jpcb.6c02574
UR - https://europepmc.org/article/MED/42915338
AB - Passive membrane permeation depends on both solute partitioning and coordinate-dependent mobility, but their separate and spatial-coupling contributions are rarely quantified within a common resistance framework. CNFD (6b,7-dihydro-5H-cyclopenta[b]naphtho[2,1-d]furan-5,6(9aH)-dione), a semisynthetic naphthoquinone with low-micromolar cytotoxicity and tumor-growth inhibition in preclinical models, was examined in a four-component model lipid bilayer. Established simulated tempering-enhanced umbrella sampling, WHAM, the Hummer positional-autocorrelation formalism, and the inhomogeneous solubility-diffusion model were combined. Three independent replicas yielded favorable interfacial partitioning (-4.66 kJ mol-1) and a positive membrane-center free energy (+12.36 kJ mol-1). Controlled profile substitutions showed that PMF heterogeneity and position-dependent diffusion amplified CNFD resistance by factors of 10.54 and 14.89, respectively, whereas their residual spatial-coupling factor was 1.134. The PMF maximum and diffusion minimum were separated by 2.14 nm. The primary intrinsic Peff was 9.09 × 10-2 cm s-1. Applying the same analysis to β-lapachone and plumbagin identified contrasting resistance regimes, with plumbagin combining a favorable center PMF with much lower central resistance localization. These results show how spatially separated free-energy and mobility landscapes govern intrinsic lipid-phase permeation.
SN - 1520-6106
SN - 1520-5207
ER -