Equilibrium sampling for biomolecules under mechanical tension.

Area of Science:

• Biophysics
• Computational Biology
• Materials Science

Background:

• Simulating force-induced biomolecular transitions is challenging due to timescale differences between experiments and simulations.
• Obtaining convergent sampling in molecular dynamics simulations remains a significant hurdle.

Purpose of the Study:

• To develop and test a novel computational approach for simulating mechanical stretching of biomolecules under equilibrium conditions.
• To improve the efficiency and accuracy of molecular dynamics simulations for studying conformational transitions.

Main Methods:

• Developed and applied a combined replica-exchange method and umbrella sampling (REM-US) approach.
• Simulated atomic force microscope (AFM) stretching and relaxing measurements on the polysaccharide pustulan ((1-->6)-beta-D-glucan).

Main Results:

• REM-US simulations achieved significantly enhanced sampling convergence and efficiency.
• The approach accurately reproduced equilibrium force-extension curves measured by AFM.
• Identical force-extension curves were generated for both stretching and relaxing simulations, confirming equilibrium conditions.

Conclusions:

• The REM-US approach provides a robust method for modeling mechanical stretching of biomolecules, including polysaccharides and nucleic acids.
• This technique allows direct acquisition of equilibrium properties without additional assumptions.
• REM-US successfully overcomes timescale limitations in molecular dynamics simulations.