Detailed potential of mean force studies on host-guest systems from the SAMPL6 challenge

Journal of Computer-aided Molecular Design
Lin Frank SongKenneth M Merz

Abstract

Accurately predicting receptor-ligand binding free energies is one of the holy grails of computational chemistry with many applications in chemistry and biology. Many successes have been reported, but issues relating to sampling and force field accuracy remain significant issues affecting our ability to reliably calculate binding free energies. In order to explore these issues in more detail we have examined a series of small host-guest complexes from the SAMPL6 blind challenge, namely octa-acids (OAs)-guest complexes and Curcurbit[8]uril (CB8)-guest complexes. Specifically, potential of mean force studies using umbrella sampling combined with the weighted histogram method were carried out on both systems with both known and unknown binding affinities. We find that using standard force fields and straightforward simulation protocols we are able to obtain satisfactory results, but that simply scaling our results allows us to significantly improve our predictive ability for the unknown test sets: the overall RMSD of the binding free energy versus experiment is reduced from 5.59 to 2.36 kcal/mol; for the CB8 test system, the RMSD goes from 8.04 to 3.51 kcal/mol, while for the OAs test system, the RSMD goes from 2.89 to 0.95 kcal/m...Continue Reading

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Citations

Nov 12, 2018·Journal of Computer-aided Molecular Design·Andrea RizziJohn D Chodera
Jan 25, 2020·Journal of Computer-aided Molecular Design·Zhaoxi SunZhengdan Zhu
Jun 26, 2020·Frontiers in Molecular Biosciences·Robert HallAlex Dickson
Oct 11, 2020·Journal of Computer-aided Molecular Design·Zhe HuaiZhaoxi Sun
Nov 6, 2020·Journal of Computer-aided Molecular Design·Yiğitcan EkenAngela K Wilson
Apr 4, 2021·International Journal of Molecular Sciences·Esra Boz, Matthias Stein
Jul 15, 2021·Journal of Chemical Theory and Computation·Martina BertazzoAndrea Cavalli
Oct 12, 2019·Journal of Chemical Theory and Computation·David R SlochowerMichael K Gilson

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