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Timestamp: 2019-04-20 09:15:16+00:00

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7These authors contributed equally to this work.
Förster Resonance Energy Transfer (FRET) based measurements that calculate the stoichiometry of intermolecular interactions in living cells have recently been demonstrated, where the technique utilizes selective one-photon excitation of donor and acceptor fluorophores to isolate the pure FRET signal. Here, we present work towards extending this FRET stoichiometry method to employ two-photon excitation using a pulse-shaping methodology. In pulse-shaping, frequency-dependent phases are applied to a broadband femtosecond laser pulse to tailor the two-photon excitation conditions to preferentially excite donor and acceptor fluorophores. We have also generalized the existing stoichiometry theory to account for additional cross-talk terms that are non-vanishing under two-photon excitation conditions. Using the generalized theory we demonstrate two-photon FRET stoichiometry in live COS-7 cells expressing fluorescent proteins mAmetrine as the donor and tdTomato as the acceptor.
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Fig. 1 (a) The scheme for two-photon FRET is shown, where the donor (mAmetrine) and acceptor (tdTomato) are selectively excited by process σ D ( 2 ) (orange arrows) and σ A ( 2 ) (red arrows) respectively, while the emission is split with a dichroic and detected with two PMTs. FRET efficiency is defined as k FRET / ( k FRET + k FL D ) for the donor, where kFRET is the rate of FRET, while k FL D (solid green arrow) is the total rate of all other radiative and non-radiative decay of donor excitation. (b) When the donor and acceptor are not associated, no FRET occurs, and a majority of the emission from the donor is collected in the donor channel (green arrow) and a majority of the acceptor emission is collected in the acceptor channel(yellow arrow). (c) When associated in a complex, FRET occurs between the donor and acceptor (dotted green arrow), resulting in increased emission from the acceptor (denoted by a longer yellow arrow) and decreased emission from the donor when excited by the donor pulse-shape (smaller green solid arrow).
Fig. 2 Experimental setup: M1–M5: mirrors, G = grating, CM = concave mirror, SLM = spatial light modulator, DM1 = 660DCXXR dichroic mirror (Chroma), DM2 = 550DCXR dichroic mirror (Chroma), OBJ = 60X 1.2 NA water immersion objective (Olympus), SP = E650SP short pass filter (Chroma), Ti:Sapph laser = Titanium:sapphire laser (Venteon Pulse:One, 650 – 1000 nm).
Fig. 3 (A) Two-photon absorption spectra with respect to transition wavelength of donor (mAmetrine, red) and acceptor (tdTomato, blue) adapted from Drobizhev et al. , and their overlap with the second harmonic of the transform-limited titanium:sapphire laser pulse (SHG(TL), black). (B) Simulated second harmonic signal for excitation of donor (red) and acceptor (blue) obtained upon applying the binary spectral phase function determined via genetic algorithm. Also shown is the second harmonic spectrum of the transform-limited pulse (black). (C) Emission spectra of donor (red) and acceptor (blue). Also shown is the transmission of the dichroic filter (black) splitting the emission into two PMT channels. (D) Experimental second harmonic spectra for excitation of donor (red) and acceptor (blue) obtained upon applying the binary spectral phase function determined via genetic algorithm. Also shown is the second harmonic spectrum of the transform-limited pulse (black).

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