Converging free energies of binding in cucurbituril and octa-acid host–guest systems from SAMPL4 using expanded ensemble simulations
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Molecular containers such as cucurbituril (CB7) and the octa-acid (OA) host are ideal simplified model test systems for optimizing and analyzing methods for computing free energies of binding intended for use with biologically relevant protein–ligand complexes. To this end, we have performed initially blind free energy calculations to determine the free energies of binding for ligands of both the CB7 and OA hosts. A subset of the selected guest molecules were those included in the SAMPL4 prediction challenge. Using expanded ensemble simulations in the dimension of coupling host–guest intermolecular interactions, we are able to show that our estimates in most cases can be demonstrated to fully converge and that the errors in our estimates are due almost entirely to the assigned force field parameters and the choice of environmental conditions used to model experiment. We confirm the convergence through the use of alternative simulation methodologies and thermodynamic pathways, analyzing sampled conformations, and directly observing changes of the free energy with respect to simulation time. Our results demonstrate the benefits of enhanced sampling of multiple local free energy minima made possible by the use of expanded ensemble molecular dynamics and may indicate the presence of significant problems with current transferable force fields for organic molecules when used for calculating binding affinities, especially in non-protein chemistries.
KeywordsExpanded ensemble Host–guest Binding free energy Molecular dynamics
The authors would like to thank the NanoSTAR Institute at the University of Virginia for an undergraduate research grant, David Mobley (UC-Irvine) for his patience and strong leadership in the SAMPL4 competition, OpenEye for sponsorship of the SAMPL4 competition, and Lyle Isaacs (University of Maryland-College Park) and Mike Gilson (UC-San Diego) for their work in preparing the host–guest systems for SAMPL4.
- 5.Isaacs L (2009) Cucurbit[n]urils: from mechanism to structure and function. Chem Commun (6):619–29Google Scholar
- 8.Moghaddam S, Yang C, Rekharsky M, Ko YH, Kim K, Inoue Y, Gilson MK (2011) New ultrahigh affinity host–guest complexes of cucurbituril with bicyclo[2.2.2]octane and adamantane guests: thermodynamic analysis and evaluation of M2 affinity calculations. J Am Chem Soc 133(10):3570–81CrossRefGoogle Scholar
- 11.Muddana HS, Fenley AT, Mobley DL, Gilson MK (2014) Blind prediction of the host–guest binding affinities from the SAMPL4 challenge. J Comput Aided Mol Des (in press)Google Scholar
- 30.Cao L, Isaacs L (2013) Absolute and relative binding affinity of cucurbituril towards a series of cationic guests. Supramol Chem. doi: 10.1080/10610278.2013.852674
- 37.Chodera JD, Shirts MR (2009) A python implementation of the multistate Bennet acceptance ratio (MBAR). https://simtk.org/home/pymbar
- 39.Boresch S, Tettinger F, Leitgeb M, Karplus M (2003) Absolute binding free energies: a quantitative approach for their calculation. J Phys Chem B 107(35):9535–9551Google Scholar