Molecular dynamics model of mechanophore sensors for biological force measurement

Sumit Mittal, Rongsheng E. Wang, Robert Ros, Alison E. Ondrus, Abhishek Singharoy

Research output: Contribution to journalArticlepeer-review

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 multiscale approach combining equilibrium and steered QM/MM molecular dynamics models to capture the chemical, mechanical, and conformational transitions underlying force activation thresholds on a nano Newton 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.

Original languageEnglish (US)
Article numbere41178
JournalHeliyon
Volume11
Issue number1
DOIs
StatePublished - Jan 15 2025

Keywords

  • Biosensors
  • DFT
  • Mechanophore
  • Polymer mechanochemistry
  • QM/MM simulations

ASJC Scopus subject areas

  • General

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