The SAMPL4 host-guest blind prediction challenge: an overview

Abstract

Prospective validation of methods for computing binding affinities can help assess their predictive power and thus set reasonable expectations for their performance in drug design applications. Supramolecular host-guest systems are excellent model systems for testing such affinity prediction methods, because their small size and limited conformational flexibility, relative to proteins, allows higher throughput and better numerical convergence. The SAMPL4 prediction challenge therefore included a series of host-guest systems, based on two hosts, cucurbit[7]uril and octa-acid. Binding affinities in aqueous solution were measured experimentally for a total of 23 guest molecules. Participants submitted 35 sets of computational predictions for these host-guest systems, based on methods ranging from simple docking, to extensive free energy simulations, to quantum mechanical calculations. Over half of the predictions provided better correlations with experiment than two simple null models, but most methods underperformed the null models in terms of root mean squared error and linear regression slope. Interestingly, the overall performance across all SAMPL4 submissions was similar to that for the prior SAMPL3 host-guest challenge, although the experimentalists took steps to simplify the current challenge. While some methods performed fairly consistently across both hosts, no single approach emerged as consistent top performer, and the nonsystematic nature of the various submissions made it impossible to draw definitive conclusions regarding the best choices of energy models or sampling algorithms. Salt effects emerged as an issue in the calculation of absolute binding affinities of cucurbit[7]uril-guest systems, but were not expected to affect the relative affinities significantly. Useful directions for future rounds of the challenge might involve encouraging participants to carry out some calculations that replicate each others' studies, and to systematically explore parameter options.

Fig. 1

Structures of cucurbit[7]uril (CB7; a) and octa-acid (OA; b). c Chemical structures of CB7 guest molecules, C1–C14, and OA guests, O1–O9. The numbering used here is consistent with that originally provided to the participants

Fig. 2

Rank ordering of submissions based on various error metrics for the CB7 and OA systems. Null models are shown in red and horizontal dotted lines are provided as visual guides to distinguish which submissions surpass the null models

Fig. 3

Binding free energy of guests for the OA system as a function of guest’s solvent accessible surface area