Jonathan R. Church1, Jogvan Magnus Haugaard Olsen2, Igor Schapiro1
1 Fritz Haber Center for Molecular Dynamics Research Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel
2 DTU Chemistry, Technical University of Denmark, DK-2800 Kongens. Lyngby, Denmark.


The impact of retinal configuration on the protein-chromophore interactions in bistable jumping spider rhodopsin-1
J. R. Church, J. M. H. Olsen, I. Schapiro, Molecules 2022, 27, 71.

Bistable rhodopsins have two stable forms that can be interconverted by light. Due to their ability to act as photoswitches, these proteins are considered as ideal candidates for applications such as optogenetics. In this work, we analyze a recently crystalized bistable rhodopsin, namely the jumping spider rhodopsin-1 (JSR1). This rhodopsin exhibits identical absorption maxima for the parent and the photoproduct form, which impedes its broad application. We performed hybrid QM/MM simulations to study three isomers of the retinal chromophore: the 9-cis, 11-cis and all-trans configurations. The main aim was to gain insight into the specific interactions of each isomer and their impact on the absorption maximum in JSR1. The absorption spectra were computed using sampled snapshots from QM/MM molecular dynamics trajectories and compared to their experimental counterparts. The chromophore-protein interactions were analyzed by visualizing the electrostatic potential of the protein and projecting it onto the chromophore. It was found that the distance between a nearby tyrosine (Y126) residue plays a larger role in the predicted absorption maximum than the primary counterion (E194). Geometric differences between the isomers were also noted, including a structural change in the polyene chain of the chromophore, as well as changes in the nearby hydrogen bonding network.


Parameters for the all-trans, 11-cis and 9-cis isomers of the retinal chromophore were derived using the mdgx program found in AmberTools 16 for use with the FF14SB force field to perform simulations on animal rhodopsins. The bond, angle and dihedral parameters as well as the atomic RESP charges for each isomer were produced using gas-phase trajectories. Each isomer of the retinal chromophore was first optimized in the gas-phase using HF/6-31G*, the lysine link including the backbone atoms were kept and the severed peptide bonds were capped using hydrogens. Next, 30 initial conditions for each con-former in the gas-phase were generated using normal mode sampling where the energy of each normal mode was sampled using a Boltzmann distribution of energies at 300 K. The trajectories were then propagated using the GAMESS-US (2018, R3) program at the HF/6-31G* level of theory for 20 fs each using a timestep of 0.5 fs. Snapshots were then generated using the resulting trajectory swarm every 1 fs and a RESP fitting was per-formed using the mdgx program in tandem with ORCA 4.2.0 at the HF/6-31G* level of theory. This resulted in the fitting of 1260 snapshots for both the 11-cis/all-trans and 9-cis/all-trans parameter sets. During the fitting the point charges of the lysine link were fixed to that of a normal lysine, except for the epsilon carbon and its hydrogens. A restraint weight of 0.005 kcal/mol was placed on the charges of all heavy atoms of the chromophore when performing the RESP fitting. Equivalent hydrogens were also restrained to have the same value in the charge fitting. The RESP charges were then used to fit the bond, angle and dihedral parameters at the B3LYP/cc-pVTZ level of theory with the RIJCOSX approximation and D3 dispersion corrections, and with a tight SCF convergence criterion. The forcefield parameters were then iterated by optimizing the original set of snapshots with the mdgx program, together with the Amber program, which generated new structures and this process was repeated until the parameters had converged. When using these novel parameters, the lysine sidechain attached to the chromophore can be linked to the rest of the peptide backbone using normal lysine FF14SB Amber force field parameters.

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