Computational Characterization of Novel Malononitrile Variants of Laurdan with Improved Photophysical Properties for Sensing in Membranes

Fluorescent probes are powerful tools
for improving our understanding
of cellular membranes and other complex biological environments. Using
simulations, we gain atomistic and electronic insights into the effectiveness
of the probes. In the current work, we have used various computational
approaches to comprehensively investigate the properties of the fluorescent
probe Laurdan and two Laurdan-like probes: AADAL and ECL. In addition,
we propose the development of their corresponding novel malononitrile
variants, which are computationally characterized herein. For the
candidate probes, electronic structure calculations were used to rationalize
their optical properties, including their ability for two-photon activation,
and molecular dynamics simulations were used to unravel atomistic
details of their functioning within lipid bilayers. While Laurdan,
AADAL, and ECL were found to have very similar optical and membrane
partitioning profiles, their malononitrile variants were found to
show significantly improved optical properties, especially in regard
to two-photon cross sections, and they appear to retain the desired
membrane characteristics of the parent Laurdan molecule.