<p>High signal-to-noise optical voltage indicators will enable
simultaneous interrogation of membrane potential in large ensembles of neurons.
However, design principles for voltage sensors with high sensitivity and
brightness remain elusive, limiting the applicability of voltage imaging. In
this paper, we use molecular dynamics (MD) simulations and density functional
theory (DFT) calculations to guide the design of a bright and sensitive
green-fluorescent voltage-sensitive fluorophore, or VoltageFluor (VF dye), that
uses photoinduced electron transfer (PeT) as a voltage-sensing mechanism. MD
simulations predict an 11% increase in sensitivity due to membrane orientation,
while DFT calculations predict an increase in fluorescence quantum yield, but a
decrease in sensitivity due to a decrease in rate of PeT. We confirm these
predictions by synthesizing a new VF dye and demonstrating that it displays the
expected improvements by doubling the brightness and retaining similar
sensitivity to prior VF dyes. Combining theoretical predictions and
experimental validation has resulted in the synthesis of the highest
signal-to-noise green VF dye to date. We use this new voltage indicator to
monitor the electrophysiological maturation of human embryonic stem
cell-derived medium spiny neurons. </p>
Photoinduced 1,2,3,4-tetrahydropyridine ring conversions
