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Issue 22, 2020
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Twisting and tilting of a mechanosensitive molecular probe detects order in membranes

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Lateral forces in biological membranes affect a variety of dynamic cellular processes. Recent synthetic efforts have introduced fluorescent “flippers” as environment-sensitive planarizable push–pull probes that can detect lipid packing and membrane tension, and respond to lipid-induced mechanical forces by a shift in their spectroscopic properties. Herein, we investigate the molecular origin of the mechanosensitivity of the best known flipper, Flipper-TR, by an extended set of molecular dynamics (MD) simulations in membranes of increasing complexity and under different physicochemical conditions, revealing unprecedented details of the sensing process. Simulations enabled by accurate refinement of Flipper-TR force field using quantum mechanical calculations allowed us to unambiguously correlate the planarization of the two fluorescent flippers to spectroscopic response. In particular, Flipper-TR conformation exhibits bimodal distribution in disordered membranes and a unimodal distribution in highly ordered membranes. Such dramatic change was associated with a shift in Flipper-TR excitation spectra, as supported both by our simulated and experimentally-measured spectra. Flipper-TR sensitivity to phase-transition is confirmed by a temperature-jump protocol that alters the lipid phase of an ordered membrane, triggering an instantaneous mechanical twisting of the probe. Simulations show that the probe is also sensitive to surface tension, since even in a naturally disordered membrane, the unimodal distribution of coplanar flippers can be achieved if a sufficiently negative surface tension is applied to the membrane. MD simulations in ternary mixtures containing raft-like nanodomains show that the probe can discriminate lipid domains in phase-separated complex bilayers. A histogram-based approach, called DOB-phase classification, is introduced that can differentiate regions of disordered and ordered lipid phases by comparing dihedral distributions of Flipper-TR. Moreover, a new sensing mechanism involving the orientation of Flipper-TR is elucidated, corroborating experimental evidence that the probe tilt angle is strongly dependent on lipid ordering. The obtained atomic-resolution description of Flipper-TR mechanosensitivity is key to the interpretation of experimental data and to the design of novel mechanosensors with improved spectroscopic properties.

Graphical abstract: Twisting and tilting of a mechanosensitive molecular probe detects order in membranes

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Supplementary files

Article information

16 Apr 2020
29 Apr 2020
First published
21 May 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020,11, 5637-5649
Article type
Edge Article

Twisting and tilting of a mechanosensitive molecular probe detects order in membranes

G. Licari, K. Strakova, S. Matile and E. Tajkhorshid, Chem. Sci., 2020, 11, 5637
DOI: 10.1039/D0SC02175J

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