Activation Mechanism of Jumping Spider Rhodopsin-1 Revealed by Classical Molecular Dynamics

Animal rhodopsins are photosensitive G-protein-coupled receptors (GPCRs) that can be classified as monostable or bistable pigments depending on whether the retinal protonated Schiff base (rPSB) remains bound or dissociates after photoisomerization. The Jumping Spider Rhodopsin-1 (JSR1) follows a photocycle in which the chromophore can be reisomerized back to the dark state, which characterizes it as bistable. This property makes them attractive for optogenetics, as it allows repeated activation without the need for external retinal supply, unlike vertebrate rhodopsins. Despite this potential, the activation mechanism of bistable rhodopsins remains less understood compared to vertebrate rhodopsins, for which multiple structures across the photocycle have been determined. Here, we address this gap by performing parallel classical molecular dynamics (MD) simulations of Jumping Spider Rhodopsin in its dark (11-cis rPSB) and active (all-trans rPSB) states, finding similarities and differences with the activation mechanism of the monostable bovine rhodopsin (Rho). Complementary hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) calculations found good agreement with spectroscopic results of JSR1.