[Folding@home] Binding Thermodynamics of Host-Guest Systems with SMIRNOFF99Frosst 1.0.5 from the Open Force Field Initia

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J Chem Theory Comput. 2019 Nov 12;15(11):6225-6242. doi: 10.1021/acs.jctc.9b00748. Epub 2019 Oct 25. ABSTRACT Designing ligands that bind their target biomolecules with high affinity and specificity is a key step in small-molecule drug discovery, but accurately predicting protein-ligand binding free energies remains challenging. Key sources of errors in the calculations include inadequate sampling of conformational space, ambiguous protonation states, and errors in force fields. Noncovalent complexes between a host molecule with a binding cavity and a druglike guest molecule have emerged as powerful model systems. As model systems, host-guest complexes reduce many of the errors in more complex protein-ligand binding systems, as their small size greatly facilitates conformational sampling, and one can choose...

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