On the NS-DSSB unidirectional estimates in the SAMPL6 SAMPLing challenge

Area of Science:

• Computational chemistry
• Molecular dynamics simulations
• Free energy calculations

Background:

• The SAMPL6 challenge assessed molecular dynamics (MD) methods for binding free energy calculations.
• The nonequilibrium switch double-system-single-box (NS-DSSB) approach showed severe errors with unidirectional estimates.
• Reproducibility and convergence of MD binding free energy methodologies are critical.

Purpose of the Study:

• To provide a clear explanation for the severe errors observed in the NS-DSSB method.
• To propose a minimal modification to the NS-DSSB protocol for accurate unidirectional estimates.
• To improve the reliability of binding free energy calculations in molecular simulations.

Main Methods:

• Analysis of the nonequilibrium switch double-system-single-box (NS-DSSB) protocol.
• Development of a modified NS-DSSB protocol for unidirectional estimates.
• Focus on ligand decoupling in the bound state and recoupling in the bulk.

Main Results:

• Identified the source of severe errors in unidirectional NS-DSSB estimates.
• Developed a straightforward modification to the NS-DSSB protocol.
• Demonstrated the potential for obtaining reliable unidirectional estimates.

Conclusions:

• The proposed modification addresses the limitations of the NS-DSSB method.
• Reliable unidirectional estimates for binding free energy are achievable with the modified protocol.
• This work contributes to the accurate assessment of molecular dynamics methodologies.