Quantum Mechanics/Molecular Mechanics Density Functional Theory Simulations of the Optical Properties Fingerprinting the Ligand-Binding of Pentameric Formyl Thiophene Acetic Acid in Amyloid-β(1–42)

The
binding pocket proposed by König [Chem. Commun. 2018, 54, 3030–3033] for the biomarker pentameric formyl thiophene
acetic acid (p-FTAA) in the fibrillar structure of amyloid-β(1–42)
has been put to the test by the comparison of theoretical and experimental
optical absorption and fluorescence spectra obtained in a water environment
and inside the protein scaffold. The optical absorption/emission properties
of this luminescent conjugated oligothiophene were studied by means
of classical force field molecular dynamics simulations to account
for the sampling of configuration space in conjunction with polarizable
embedding time-dependent density functional theory calculations of
spectra. The nuclear motions of residues in the β-sheet were
found to be modest, and the time dependence of embedding parameters
was shown to be negligible so that a time-independent parameter set
could be derived and used for all 300 snapshots considered in the
spectrum averaging. In regard to linear absorption spectra, the calculated
red shift due to protein binding for the dominant S1 ← S0 transition in
p-FTAA was found to be equal to 23 nm (0.17 eV), which is in excellent
agreement with the corresponding experimental result of 18 nm and
taken as corroborating evidence for having correctly identified the
binding pocket of p-FTAA in the amyloid. The underlying mechanisms
for the calculated red shift were disentangled, and it is shown that
some 20 nm (0.15 eV) of the total 23 nm (0.17 eV) is associated with
increased planarity of p-FTAA in the binding pocket, whereas a mere
3 nm (0.02 eV) is associated with changes in the environment. In regard
to emission spectra, we demonstrate that intersystem crossing from
the excited S1 state to the triplet manifold
of states is a less likely event for p-FTAA in the binding pocket
as compared to in the aqueous solution, and we thereby partly explain
the much higher quantum yield of fluorescence for the more rigid p-FTAA
in the binding pocket. Two-photon absorption in p-FTAA is shown to
predominantly occur to an overall symmetric excited state and be more
than twice as strong for the biomarker in the binding pocket as compared
to in water. The corresponding red shift, on the other hand, is very
small. Earlier experimental two-photon fluorescence imaging using
p-FTAA is shown not to target the dominant two-photon state, and ways
to reach a higher image quality (lower signal-to-noise ratio) are
proposed in terms of tuning the laser wavelength toward the region
of 600 nm or the synthesis of asymmetric ligands with S1 states that are both one- and two-photon allowed.