Molecular simulation approaches to probing the effects of mechanical forces in the actin cytoskeleton.

In this article we give our perspective on the successes and promise of various molecular and coarse-grained simulation approaches to probing the effect of mechanical forces in the actin cytoskeleton.

Efficient Discovery of Visible Light-Activated Azoarene Photoswitches with Long Half-Lives Using Active Search.

Photoswitches are molecules that undergo a reversible, structural isomerization after exposure to certain wavelengths of light. The dynamic control offered by molecular photoswitches is favorable for materials chemistry, photopharmacology, and catalysis applications. Ideal photoswitches absorb visible light and have long-lived metastable isomers. We used high-throughput virtual screening to predict the absorption maxima (λmax) of the E-isomer and half-life (t1/2) of the Z-isomer. However, computing the photophysical and kinetic stabilities with density functional theory of each entry of a virtual molecular library containing thousands or millions of molecules is prohibitively time-consuming. We applied active search, a machine-learning technique, to intelligently search a chemical search space of 255 991 photoswitches based on 29 known azoarenes and their derivatives. We iteratively trained the active search algorithm on whether a candidate absorbed visible light (λmax > 450 nm). Active search was found to triple the discovery rate compared to random search. Further, we projected 1962 photoswitches to 2D using the Uniform Manifold Approximation and Projection algorithm and found that λmax depends on the core, which is tunable by substituents. We then incorporated a second stage of screening to predict the stabilities of the Z-isomers for the top candidates of each core. We identified four ideal photoswitches that concurrently satisfy the following criteria: λmax > 450 nm and t1/2 > 2 h.These candidates had λmax and t1/2 range from 465 to 531 nm and hours to days, respectively.

Photophysical Tuning of Shortwave Infrared Flavylium Heptamethine Dyes via Substituent Placement.

Optical imaging in the shortwave infrared region (SWIR, 1000-2000 nm) provides high-resolution images in complex systems. Here we explore substituent placement on dimethylamino flavylium polymethine dyes, a class of SWIR fluorophores. We find that the position of the substituent significantly affects the λmax and fluorescence quantum yield. Quantum-mechanical calculations suggest that steric clashes control the extent of π-conjugation. These insights provide design principles for the development of fluorophores for enhanced SWIR imaging.