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Quantitative Estimation of Cyclotide-Induced Bilayer Membrane Disruption by Lipid Extraction with Mesoscopic Simulation
preprintsubmitted on 01.03.2021, 16:57 and posted on 03.03.2021, 10:44 by Karina van den Broek, Matthias Epple, Lisa Sophie Kersten, Hubert Kuhn, Achim Zielesny
Cyclotide-induced membrane disruption is studied at the microsecond timescale by Dissipative Particle Dynamics (DPD) to quantitatively estimate a kinetic rate constant for membrane lipid extraction with a “sandwich” interaction model where two bilayer membranes enclose a cyclotide/water compartment. The obtained bioactivity trends for cyclotides Kalata B1, Cycloviolacin O2 and selected mutants with different membrane types are in agreement with experimental findings: For all membranes investigated, Cycloviolacin O2 shows a higher lipid extraction activity than Kalata B1. The presence of cholesterol leads to a decreased cyclotide activity compared to cholesterol-free membranes. Phosphoethanolamine-rich membranes exhibit an increased membrane disruption. A cyclotide’s “hydrophobic patch” surface area is important for its bioactivity. A replacement of or with charged amino acid residues may lead to super-mutants with above-native activity but without simple charge-activity patterns. Cyclotide mixtures show linearly additive bioactivities without significant sub- or over-additive effects.