Low-mass molecular dynamics simulation: a simple and generic technique to enhance configurational sampling

Area of Science:

• Biophysics
• Computational Biology
• Protein Dynamics

Background:

• CLN025 is a small, fast-folding protein.
• Autonomous folding of CLN025 in molecular dynamics (MD) simulations has not been previously reported.
• Understanding protein folding mechanisms is crucial in quantitative biology.

Purpose of the Study:

• To report the autonomous folding of CLN025 in classical, all-atom, isothermal-isobaric MD simulations.
• To demonstrate the efficacy of low-mass MD simulations for enhancing configurational sampling.
• To explore the potential of this technique for studying miniature protein folding.

Main Methods:

• Utilized AMBER forcefield derivatives with a 10-fold reduction in atomic masses.
• Performed multiple 500-ns MD simulations at 277K and 1 atm in explicit solvent.
• Compared results with simulations using original AMBER forcefields (FF12SB, FF14SB).

Main Results:

• Observed autonomous and repeated folding of CLN025 from extended to native conformation.
• The first folding event occurred as early as 66.1 ns.
• No folding events were observed using original AMBER forcefields.

Conclusions:

• Low-mass MD simulation is a simple and effective technique for enhancing configurational sampling.
• This method can facilitate the autonomous folding of miniature proteins in classical MD.
• The findings represent a significant advancement for quantitative biology and protein folding research.