Composition-Dependent Remodeling of the ABCB1Disordered Linker by Plasma-Generated ReactiveMixtures
- 1Faculty of Physics and Energy Engineering, Amirkabir University of Technology, P.O. Box 15875-4413, Tehran, Iran
Abstract
Multidrug resistance (MDR) mediated by the efflux transporter ABCB1 (P-glycoprotein) remains a major barrier in cancer chemotherapy. Because classical active-site inhibitors have largely failed clinically due to off-target toxicity, disrupting the interdomain mechanical coupling required for transport has emerged as an attractive alternative. Cold atmospheric plasma (CAP) generates coexisting reactive oxygen and nitrogen species (RONS) capable of sensitizing chemoresistant cells, yet how multicomponent reactive mixtures dynamically perturb the intrinsically disordered NBD1–TMD2 linker, a vital mechanical relay in ABCB1, remains unresolved. Here, we investigate the conformational and mechanical response of the structurally tethered ABCB1 linker exposed to binary and ternary mixtures of H2O2, NO, and O2 using all-atom molecular dynamics simulations. Characterization across a six-descriptor dynamical panel, synthesized into an Integrated Control-Relative Restriction Score (ICRRS), reveals that linker remodeling is governed by chemical composition rather than total molecular loading. Increasing molecular burden does not induce monotonic rigidity; instead, distinct mixture combinations selectively direct the linker toward divergent, polarized states of conformational restriction or conformational release. Crucially, benchmarking against isolated-species counterparts revealed pronounced composition-dependent contrasts, wherein co-solutes redirect local torsional kinetics, spatial breadth, and effective tethered stiffness. These findings establish that coexisting plasma-derived species selectively reconfigure the conformational state of the ABCB1 disordered relay. By demonstrating that mixture biophysics overrides concentration-dependent loading, this work provides an atomistic foundation for how multicomponent plasma biophysics can mechanically modulate ABCB1 allostery, offering new biophysical perspectives for overcoming P-glycoprotein-mediated chemoresistance.
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BibTeX
@misc{hoseini2026compositiondependent,
title = {{Composition-Dependent Remodeling of the ABCB1Disordered Linker by Plasma-Generated ReactiveMixtures}},
author = {Mansoureh Hoseini and Hossein Abbasi},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010176/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010176/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Composition-Dependent Remodeling of the ABCB1Disordered Linker by Plasma-Generated ReactiveMixtures
AU - Mansoureh Hoseini
AU - Hossein Abbasi
PY - 2026
DA - 2026/10/09
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010176/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010176/v1
AB - Multidrug resistance (MDR) mediated by the efflux transporter ABCB1 (P-glycoprotein) remains a major barrier in cancer chemotherapy. Because classical active-site inhibitors have largely failed clinically due to off-target toxicity, disrupting the interdomain mechanical coupling required for transport has emerged as an attractive alternative. Cold atmospheric plasma (CAP) generates coexisting reactive oxygen and nitrogen species (RONS) capable of sensitizing chemoresistant cells, yet how multicomponent reactive mixtures dynamically perturb the intrinsically disordered NBD1–TMD2 linker, a vital mechanical relay in ABCB1, remains unresolved. Here, we investigate the conformational and mechanical response of the structurally tethered ABCB1 linker exposed to binary and ternary mixtures of H2O2, NO, and O2 using all-atom molecular dynamics simulations. Characterization across a six-descriptor dynamical panel, synthesized into an Integrated Control-Relative Restriction Score (ICRRS), reveals that linker remodeling is governed by chemical composition rather than total molecular loading. Increasing molecular burden does not induce monotonic rigidity; instead, distinct mixture combinations selectively direct the linker toward divergent, polarized states of conformational restriction or conformational release. Crucially, benchmarking against isolated-species counterparts revealed pronounced composition-dependent contrasts, wherein co-solutes redirect local torsional kinetics, spatial breadth, and effective tethered stiffness. These findings establish that coexisting plasma-derived species selectively reconfigure the conformational state of the ABCB1 disordered relay. By demonstrating that mixture biophysics overrides concentration-dependent loading, this work provides an atomistic foundation for how multicomponent plasma biophysics can mechanically modulate ABCB1 allostery, offering new biophysical perspectives for overcoming P-glycoprotein-mediated chemoresistance.
ER -