This paper presents the polarizable quantum mechanics/molecular mechanics (QM/MM) embedding of state-averaged complete active space self-consistent field (SA-CASSCF) in the atomic multipole optimized energetics for biomolecular applications (AMOEBA) force field for the purpose of studying photoreactions in protein environments. We describe two extensions of our previous work that combines SA-CASSCF with AMOEBA water models allowing it to be generalized to AMOEBA models for proteins and other macromolecules. First, we discuss how our QM/MM model accounts for the discrepancy between the direct and polarization electric field that arises in the AMOEBA description of intramolecular polarization. A second improvement is the incorporation of double link-atom schemes to treat instances where the QM/MM boundary goes through covalent bonds. The new SA-CASSCF/AMOEBA method is applied to an elementary reaction step in NanoLuc, an artificial bioluminescence luciferase. We will show how the reaction mechanism is different when calculated in the gas phase, in polarizable continuum medium (PCM), versus in protein AMOEBA models. 

This paper presents the state-averaged complete active space self-consistent field (SA-CASSCF) in AMOEBA polarizable water model, which enables rigorous simulation of non-adiabatic molecular dynamics with nonequilibrium solvation effects. When comparing the newly implemented AMOEBA with other solvent models (including PCM and fixed charge forcefield) for simulating photodynamics, AMOEBA is the only model that can capture a wide range of solvent effects, including the nonequilibrium electrostatic effects, hydrogen bonding, friction and steric hindrance. The paper also presents non-adiabatic molecular dynamics simulations of the model retinal protonated Schiff base molecule in water, where ultrafast transition to the ground state is observed.

In this paper, a new theoretical method is developed that enables simulating polarization effects of solvents over excited state dynamics for the first time. When applying the new method to dipolar merocyanine dye, the theoretical simulations revealed how the barrier heights of photoreaction pathways can be tuned with polarity of solvents, leading to systematic control of excited state lifetime. In another application to green fluorescent protein chromophore, the theoretical simulations show that the geometry and the shape of the conical intersection in solvents are qualitatively changed compared to in the gas phase, suggesting non-trivial solvation effects over excited state dynamics in photoreactions.