Multiscale Responsive Kinetic Modeling: Quantifying Biomolecular Reaction Flux under Varying Electrochemical...

Area of Science:

• Molecular Biophysics
• Computational Biology
• Biochemistry

Background:

• Characterizing complex molecular processes with multiple transitions is challenging, especially under varying conditions.
• Understanding the kinetics and thermodynamics of these processes is crucial for molecular biophysics.

Purpose of the Study:

• To develop a condition-responsive kinetic modeling framework.
• To integrate multiscale simulations with experimental data for accurate kinetic solutions.
• To apply and validate the framework for electrochemically driven transport in channels and transporters.

Main Methods:

• Developed a condition-responsive kinetic modeling framework.
• Combined bottom-up rate quantification from multiscale simulations with top-down solution refinement.
• Utilized experimental data, including electrophysiology assays, for refinement.
• Applied the framework to the ClC-ec1 antiporter and Shaker K+ channel.

Main Results:

• Demonstrated robust and predictive kinetic solutions for ion transport.
• Showcased the framework's ability to ground solutions with thermodynamic constraints.
• Successfully refined kinetic models using experimental data.
• Identified dominant mechanisms while highlighting the importance of competing and off-pathway fluxes.

Conclusions:

• The developed framework enables comprehensive thermodynamic and kinetic characterization of complex molecular processes.
• It provides a powerful tool for studying ion transport in channels and transporters under various conditions.
• Accurate modeling requires integrating simulation-based quantification with experimental validation.