How Fast Is Too Fast in Force-Probe Molecular Dynamics Simulations?

Area of Science:

• Biophysics
• Computational Biology
• Protein Dynamics

Background:

• Molecular dynamics (MD) simulations interpret atomic force microscopy (AFM) experiments of protein unfolding.
• Discrepancies in loading rates and timescales between MD and AFM pose challenges.
• The impact of high MD pulling velocities on protein unfolding sequence bias is not well understood.

Purpose of the Study:

• To quantify the bias in protein unfolding sequences due to high pulling velocities in MD simulations.
• To investigate the relationship between pulling velocity and preferential unfolding of specific protein regions.
• To determine the effective signal propagation speed associated with this unfolding bias.

Main Methods:

• Utilized molecular dynamics simulations of four tandem spectrin repeats (SRs) with poly-glycine linkers.
• Applied seven different pulling velocities ranging from 0.01 to 10 m/s.
• Analyzed unfolding sequences and partial unfolding events at various simulation speeds.

Main Results:

• At high velocities (≥ 1 m/s), outer domains preferentially unfold, observed in 100% of simulations at 10 m/s.
• The unfolding bias is equivalent to an effective signal propagation speed of 5-100 m/s.
• This effective speed is approximately two orders of magnitude slower than the speed of sound.

Conclusions:

• High pulling velocities in MD simulations introduce a significant bias in protein unfolding sequences.
• This bias affects the order of domain unfolding, favoring outer domains.
• Understanding and accounting for this bias is crucial for accurate interpretation of MD simulations of protein unfolding.