Year: 2023
Type: preprint
Abstract: Cellular forces regulate an untold spectrum of living processes such as cell migration, gene expression, and ion conduction. However, a quantitative description of mechanical control remains elusive due to the lack of general, live-cell tools to measure discrete forces between biomolecules. Here we introduce a computational pipeline for force measurement that leverages well-defined, tunable release of a mechanically activated small molecule fluorophore. These sensors are characterized using a consensus approach combining equilibrium and steered QM/MM molecular dynamics models to capture the chemical, mechanical, and conformational transitions underlying force activation thresholds on a pico-to-nanonewton scale. We find that chemical modification of the mechanophore and variation of its biomolecular tethers can tune the rate-determining step for fluorophore release and adjust the mechanochemical activation barrier. The models offer a new molecular framework for calibrated, programmable biomolecular force reporting within the live-cell regime, opening new opportunities to study mechanical phenomena in biological systems
Source: ChemRxiv
Language: English
Subfield: Polymers and Plastics
Field: Materials Science
Domain: Physical Sciences
Open Access status: green
Awards: CAREER: Data-driven computations to infer chemomechanical coupling from cryo-electron microscopy and support zero-cost online biophysics programs in high schools, G546177184, Dynamics of membrane proteins unraveled by time-resolved serial crystallography, G5986892838, G6671297155, CAREER: Chemical Probes to Interrogate Real-Time Cellular Activity of Lysine-based Post-translational Modification Erasers, G7708335152, G8438342018
OpenAlex ID: W4387741176