Photophysics of\nMolecular Probes for Amyloid‑β\nDetection: Computational Insights into the Roles of Probe Linker and\nFunctional Groups

In this computational study, density functional theory\n(DFT) and\ntime-dependent DFT methods (TD-DFT) were employed to study the optical\nproperties of six families of molecules with donor (D), bridge (B),\nand acceptor (A) fragments that have potential for use as fluorescent\nmolecular probes for the early detection of Alzheimer′s disease.\nAfter validating our computational method against experimental data,\nusing X-ray and absorption data, the equilibrium geometries and wave\nfunctions of the ground and first singlet excited states were systematically\nstudied. Our simulations demonstrate that the S<sub>1</sub> states\nof these rod-like D–B–A fluorescent probes are twisted\nintramolecular charge transfer states with a predominant highest occupied\nmolecular orbital–least unoccupied molecular orbital (HOMO–LUMO)\ncharacter, the former localized primarily at the donor, whereas the\nlatter at the acceptor site. Moreover, the influence of the bridge,\ndonor, and acceptor fragments on molecules’ absorption energies\nis explored, highlighting the influence of double and triple bonds\nand some specific modifications on the acceptor side, including the\naddition of electronegative atoms, pyranone derivatives, and their\nfunctionalization. By having the absorption energies of 324 probes\nin hand, machine learning models were trained to predict the absorption\nenergies of molecules. The models were found to be predictive, which\nsuggests a potential that predictive models for other crucial properties,\nsuch as emission and quantum yield, can also be trained if suitable\ntraining data sets are made available.