Rotation Kinetics of Molecular Motors Influence Their Ability to Kill Cancer Cells and Induce Cellular Calcium Signaling

Although chemical agents have long been the primary method for influencing cellular behavior, mechanical forces also play an important role in many cellular processes. Most mechanical forces are applied externally to cell membranes. However, it has recently been demonstrated that mechanical forces can be applied to cells from within using synthetic molecular motors (MMs). MMs mechanically influence their environment by undergoing rapid unidirectional rotation when irradiated with light. The activation of MMs in cell membranes can lead to various effects, ranging from cell death when activated for minutes to intracellular calcium signaling when activated for <1 s. The purpose of this study is to investigate the structure-function relationships governing the effectiveness of MMs in several different biological applications. We do this by synthesizing four nearly identical MMs, where we modify the functional group that significantly influences MM rotation to contain either a methyl, isopropyl, <i>tert</i>-butyl, or phenyl group. We use density functional theory (DFT) calculations to determine the relative rotation rates of the four MMs and reveal that the methylated MM is the fastest, while bulkier substituents result in slower rotation. The MM with a methyl substituent is the most effective at killing cells and inducing intracellular calcium signaling. This study reinforces the idea that MMs influence cellular environments primarily through unidirectional molecular rotation, and it further demonstrates that internal mechanical forces can controllably induce cell activity.