SAMPL9 blind predictions using nonequilibrium alchemical approaches

Abstract

We present our blind predictions for the Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL), ninth challenge, focusing on the binding of WP6 (carboxy-pillar[6]arene) with ammonium/diammonium cationic guests. Host–guest binding free energies have been calculated using the recently developed virtual double system single box approach, based on the enhanced sampling of the bound and unbound end-states followed by fast switching nonequilibrium alchemical simulations [M. Macchiagodena et al., J. Chem. Theory Comput. 16, 7160 (2020)]. As far as Pearson and Kendall coefficients are concerned, performances were acceptable and, in general, better than those we submitted for calixarenes, cucurbituril-like open cavitand, and beta-cyclodextrines in previous SAMPL host–guest challenges, confirming the reliability of nonequilibrium approaches for absolute binding free energy calculations. In comparison with previous submissions, we found a rather large mean signed error that we attribute to the way the finite charge correction was addressed through the assumption of a neutralizing background plasma.