A computational study of light-induced superimposed mechanical and dipolar effects

Abstract

Light-sensitive molecules provide a powerful means to control cellular excitability without genetic modification. Among them, the amphiphilic membrane targeting azobenzene Ziapin2 has emerged as a versatile photo-switch able to modulate membrane potential. Previous studies have attributed its action mainly to an opto-mechanical effect. However, azobenzenes are known to undergo significant light-induced dipole changes, raising the possibility of additional electrical contributions. Here, we combine experimental data and numerical modeling to investigate this dual mechanism in Ziapin2. Our analysis shows that beyond capacitance modulation, a substantial increase in molecular dipole moment (> 6D) can shift membrane surface potential, partially counteracting the hyperpolarizing effect. A model with time-varying surface potential captures key features of published responses and shows that polarity is governed by the membrane interface at which the photo-dipole is expressed, not by the dipole change alone. This combined framework provides a more complete description of Ziapin2 action and enables prospective design of next-generation molecules with tailored selective depolarizing or hyperpolarizing response.

Fig. 1

Molecular structures and dipoles. DFT calculation of the trans- to cis-variation of the dipole moment of representative molecular models of Ziapin2 (A) and MTP2 (B). Adapted from Sesti et al. [13]

Fig. 2

Membrane potential variation. (A) V_m variation over time upon 20 ms light stimulation with (blue) and without (orange) considering the variation of V_s. (B) Capacitance and (C) surface potential variation over time

Fig. 3

Effect of resting potential and V_s polarity. (A) Membrane potential traces for holding potentials from − 35 to − 85 mV in the two-pathway model. (B) Amplitude of light-induced hyperpolarization as a function of V_r, in HEK-293T loaded with Ziapin2 (25 μM) and stimulated with 470 nm light pulses of 20 ms at 50 mW/mm². The dashed line represents the linear regression curve of the plotted data points (R² = 0.45). (C) Membrane potential traces considering a positive (blue), negative (yellow) and null (orange) variation of V_s. (D) Representative experimental trace of HEK-293T (V_r = − 21 mV) loaded with Ziapin2 (25 μM) and stimulated with 470 nm light pulses of 20 ms at 50 mW/mm². All traces have been zeroed for representation purposes