Unraveling the Ultrafast Photodynamics of Molecular Photoswitches in β-Adrenergic Receptors by First-Principles Nonadiabatic Dynamics Simulations

Understanding how protein environments regulate the photodynamics of chromophores is a central task in quantum biology and remains a major challenge. This challenge is particularly significant for G protein-coupled receptors (GPCRs), which are natively nonphotochromic but can be optically controlled via synthetic photoswitchable ligands. Such artificial photoreceptors are new and important because they not only enable the photocontrol of signaling processes beyond those regulated by rhodopsins but also deepen our fundamental understanding of quantum effects in light-protein interactions. However, the ultrafast nonadiabatic dynamics of these ligands in GPCRs remain difficult to resolve experimentally, while traditional computational approaches fail to describe these processes accurately and efficiently. Here, we employed a multiscale framework to comprehensively characterize how receptor binding, mutations, receptor subtype, chemical substitution, and binding pocket electrostatics regulate the photodynamics of photoswitchable antagonists (OPs) of β-adrenergic receptors (β-ARs). This framework integrates extensive first-principles ground-state conformational sampling, absorption-spectra calculations, and nonadiabatic dynamics simulations. Chemical substitutions influence how excitation energy, excited-state lifetimes, and quantum yields (QY) respond to receptor binding, subtype changes, and binding-pocket mutations. The F289A and Y199A mutants generally accelerate excited-state dynamics by reducing local contacts, whereas the D113E mutation slows the dynamics of OP2 in β2-ΑR by reducing the excited-state driving force. Neutralizing the charge of the counterion D113 residue via protonation increases the QY of OP2 in β2-ΑR by altering the local electrostatic and hydrogen-bonding environment. The ultrafast photoisomerization of the ligands does not require large binding-pocket expansion. Overall, this work provides new insights into how binding-pocket environments regulate the photochemical properties of photoswitchable ligands targeting GPCRs.