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A., 1994, 91, 12501–12504 CrossRef CAShttps://doi.org/10.1039/C5CP03875Hhttps://pubs.rsc.org/en/content/articlepdf/2015/cp/c5cp03875hالوصف Two-photon spectroscopy of fluorescent proteins is a powerful bio-imaging tool characterized by deep tissue penetration and little damage. However, two-photon spectroscopy has lower sensitivity than one-photon microscopy alternatives and hence a protein with a large two-photon absorption cross-section is needed. We use time-dependent density functional theory (TD-DFT) at the B3LYP/6-31+G(d,p) level of theory to screen twenty-two possible chromophores that can be formed upon replacing the amino-acid Tyr66 that forms the green fluorescent protein (GFP) chromophore with a non-canonical amino acid. A proposed chromophore with a nitro substituent was found to have a large two-photon absorption cross-section (29 GM) compared to other fluorescent protein chromophores as determined at the same level of theory. Classical molecular dynamics are then performed on a nitro-modified fluorescent protein …enphoton absorptionArticlehttps://doi.org/10.1039/C5CP03875H