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

In the context of the recent SAMPL6 SAMPLing challenge (Rizzi et al. 2020 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.

Automated summary

In the recent SAMPL6 SAMPLing challenge, a simple explanation for the errors observed in the NS-DSSB approach when using unidirectional estimates was proposed, along with a suggestion for a straightforward modification of the protocol to obtain reliable unidirectional estimates for the decoupling and recoupling process of the ligand.