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.

Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry

“…This is one area where the supramolecular and physical communities are beginning to overlap fruitfully. Indeed, host-guest systems are playing an important role in improving computation, [55][56][57] for example through the Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL) blind challenge (run in part by the Drug Design Data Resource (D3R)) which has provided an opportunity for modelers to predict the affinity of guests for proteins and synthetic hosts. 52,56,57 These challenges are extremely valuable not just to improve modeling, but also to learn how to actually gain insight; if a simulation model yields correct affinities, how is it determined which of the observed interactions are key to controlling affinity and which are incidental?…”

“…The Drug Design Data Resource is a case in point, as is the related SAMPL series of challenges. [55][56][57]63 Irrespective of the rationale for gathering the data, ΔG calibration data standards (c.f. MS calibrants) for host-guest chemistry may be very useful.…”

Advanced Potential Energy Surfaces for Molecular Simulation

“…The overall system and the numbering of the guests is the same is used for the SAMPL4 exercise. 144 The shaded region includes data points within 1.5 kcal/mol of the experimental free energy value. His research interests include ab initio molecular dynamics studies of the transport of charge defects in hydrogenbonded media, development of efficient path integral molecular dynamics methods, which he has applied in studies of proton and hydroxide transport and to hydrogen-storage materials, and development of enhanced sampling techniques for studying polymorphism in molecular crystals, for predicting conformational equilibria, and for mapping multidimensional free energy landscapes of complex molecules.…”

Statistical Mechanics of Ligand–Receptor Noncovalent Association, Revisited: Binding Site and Standard State Volumes in Modern Alchemical Theories

“…It has become increasingly clear that a microscopic description of the solvent is a crucial ingredient to reliably rank the affinity of putative ligands for a given target. 1,2 In the framework of atomistic molecular dynamics (MD) simulations with explicit solvent, several methods for rigorously determining the absolute binding free energy in noncovalently bonded systems have been devised. Most of these methodologies are based on the socalled alchemical route 3−5 (see refs 6−9 for recent reviews).…”