Free Energy Computation for an Isomerizing Chromophore in a Molecular Cavity via the Average Solvent Electrostatic Configuration Model: Applications in Rhodopsin and Rhodopsin-Mimicking Systems

Abstract

We present a novel technique for computing the free energy differences between two chromophore "isomers" hosted in a molecular environment (a generalized solvent). Such an environment may range from a relatively rigid protein cavity to a flexible solvent environment. The technique is characterized by the application of the previously reported "average electrostatic solvent configuration" method, and it is based on the idea of using the free energy perturbation theory along with a chromophore annihilation procedure in thermodynamic cycle calculations. The method is benchmarked by computing the ground-state room-temperature relative stabilities between (i) the cis and trans isomers of prototypal animal and microbial rhodopsins and (ii) the analogue isomers of a rhodopsin-like light-driven molecular switch in methanol. Furthermore, we show that the same technology can be used to estimate the activation free energy for the thermal isomerization of systems i−ii by replacing one isomer with a transition state. The results show that the computed relative stability and isomerization barrier magnitudes for the selected systems are in line with the available experimental observation in spite of their widely diverse complexity.

Ionic Atmosphere Effect on the Absorption Spectrum of a Flavoprotein: A Reminder to Consider Solution Ions

“…ASEC-FEG Calculations. The ASEC-FEG method and theory have been previously described largely for molecules in solution , and for retinal proteins. , However, we briefly describe the theory and the methodology as applied here to flavoproteins. Overall, the goal of ASEC is to account for sampling of the protein and solvent environment without substantially increasing the computational cost of QM/MM calculations.…”

“…ASEC-FEG combines the idea of the average solvent electrostatic configuration model, , originally developed to study molecular systems in solution, and the free energy gradient method proposed by Nagaoka et al − ASEC-FEG has been extended to proteins by including van der Waals average interaction energy , and has recently been extended to model flavoproteins . Therefore, the word “solvent” in ASEC really encompasses both the solvent and protein.…”

Rhodopsins: An Excitingly Versatile Protein Species for Research, Development and Creative Engineering

“…Optical spectroscopy : Butt, (1990); Ogonah et al (1991); Chizhov et al (1996); Inoue et al (2004); Rupenyan et al (2008) particular (Schapiro et al, 2011;Gozem et al, 2017;Schnedermann et al, 2018;Agathangelou et al, 2021;Nikolaev et al, 2021).…”

“…Crystal structures have been resolved for all photo-intermediates and present a broad structural basis ( Table 4 ). The power of theoretical and quantum-chemical calculations has grown immensely, laying a strong foundation for electronic and energetic elements of the process, in particular ( Schapiro et al, 2011 ; Gozem et al, 2017 ; Schnedermann et al, 2018 ; Agathangelou et al, 2021 ; Nikolaev et al, 2021 ).…”

“…This further inspired detailed analysis with modified and/or labeled retinals ( 13 C, 2 H, F) and protein residues ( 13 C, 15 N, F, azido, spin labels) using fluorescence, vibrational, EPR and NMR spectroscopy ( Table 5 ). This profited from as well as steered development of sophisticated theoretical and in-silico procedures, like DFT, QM/MM and molecular dynamics ( Altun et al, 2008 ; Collette et al, 2018 ; Del Carmen Marín et al, 2019b ; Dokukina et al, 2019 ; Pieri et al, 2019 ; Shao et al, 2020 ; Nikolaev et al, 2021 ; Scholz and Neugebauer, 2021 ; Shen et al, 2021 ; Pedraza-González et al, 2022 ). All these elements have already profoundly deepened our insight into the structure and mechanism of bovine rod rhodopsin and bacteriorhodopsin, the frontrunners of type-2 and -1, respectively.…”