#5803. On the NS-DSSB unidirectional estimates in the SAMPL6 SAMPLing challenge

July 2026publication date
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Journal’s subject area:
Physical and Theoretical Chemistry;
Computer Science Applications;
Drug Discovery;
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Abstract:
In the context of the recent SAMPL6 SAMPLing challenge (Rizzi et al. 20XX in J Comput Aided Mol Des 34:601–633) aimed at assessing convergence properties and reproducibility of molecular dynamics binding free energy methodologies, we propose a simple explanation of the severe errors observed in the nonequilibrium switch double-system-single-box (NS-DSSB) approach when using unidirectional estimates. At the same time, we suggest a straightforward and minimal modification of the NS-DSSB protocol for obtaining reliable unidirectional estimates for the process where the ligand is decoupled in the bound state and recoupled in the bulk.
Keywords:
Binding free energy; Crooks theorem; Double-system/single-box; Jarzynski identity; Non-equilibrium; SAMPL6

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