Binding free energies in the SAMPL5 octa-acid host\u2013guest challenge calculated with DFT-D3 and CCSD(T)

Octav Caldararu,Ulf Ryde,Martin A Olsson,Christoph Riplinger,Frank Neese

doi:10.1007/s10822-016-9957-5

Abstract

We have tried to calculate the free energy for the binding of six small ligands to two variants of the octa-acid deep cavitand host in the SAMPL5 blind challenge. We employed structures minimised with dispersion-corrected density-functional theory with small basis sets and energies were calculated using large basis sets. Solvation energies were calculated with continuum methods and thermostatistical corrections were obtained from frequencies calculated at the HF-3c level. Care was taken to minimise the effects of the flexibility of the host by keeping the complexes as symmetric and similar as possible. In some calculations, the large net charge of the host was reduced by removing the propionate and benzoate groups. In addition, the effect of a restricted molecular dynamics sampling of structures was tested. Finally, we tried to improve the energies by using the DLPNO–CCSD(T) approach. Unfortunately, results of quite poor quality were obtained, with no correlation to the experimental data, systematically too positive affinities (by ~50 kJ/mol) and a mean absolute error (after removal of the systematic error) of 11–16 kJ/mol. DLPNO–CCSD(T) did not improve the results, so the accuracy is not limited by the energy function. Instead, four likely sources of errors were identified: first, the minimised structures were often incorrect, owing to the omission of explicit solvent. They could be partly improved by performing the minimisations in a continuum solvent with four water molecules around the charged groups of the ligands. Second, some ligands could bind in several different conformations, requiring sampling of reasonable structures. Third, there is an indication the continuum-solvation model has problems to accurately describe the binding of both the negatively and positively charged guest molecules. Fourth, different methods to calculate the thermostatistical corrections gave results that differed by up to 30 kJ/mol and there is an indication that HF-3c overestimates the entropy term. In conclusion, it is a challenge to calculate binding affinities for this octa-acid system with quantum–mechanical methods.

Highlights

One of the most important challenges for computational chemistry is to accurately predict the free energy for the binding of a small molecule to a biomacromolecule
In this paper we present our attempts to predict the binding affinity for two variants of the octa-acid host–guest system [28] included in the SAMPL5 challenge (Fig. 1) [29]
2.0 explicit water molecules (Wat). Results with both the NOH and NOM hosts are given that structures optimised in vacuum or with conductor-like solvent model (COSMO) solvation gave similar binding energies in SAMPL4 [27]

Summary

Introduction

One of the most important challenges for computational chemistry is to accurately predict the free energy for the binding of a small molecule to a biomacromolecule. This could involve the binding of a drug candidate to its target receptor, having obvious applications in pharmaceutical chemistry. Protein–ligand complexes are very large, involving thousands of atoms and often present major problems in predicting binding affinities, e.g. owing to conformational changes of the protein during ligand binding or changes in the protonation states of the ligand and the receptor. The binding of small molecules to such systems involve the same type of interactions as protein– ligand binding, allowing the study of ligand binding in a simpler context. There has been quite some interest in such host–guest systems in recent years [15,16,17,18,19,20]

Objectives

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Results

Discussion

Conclusion