How to simulate affinities for host–guest systems lacking binding mode information: application to the liquid chromatographic separation of hexabromocyclododecane stereoisomers

Abstract

A novel approach for the simulation of host-guest systems by systematically scanning the host molecule's orientations within the guest cavity is presented along with a thermodynamic strategy for determining preferential binding modes and corresponding optimal interaction energies between host and guest molecules. By way of example, the elution order of hexabromocyclododecane stereoisomers from high performance liquid chromatography separation on a permethylated β-cyclcodextrin stationary phase has been computed using classical molecular dynamics simulations with the explicit solvents water and acetonitrile. Comparison of estimated with experimental separation data reveals remarkable squared coefficients of correlation with R(2) = 0.87 and a very high correlation R(LOO2) = 0.72 using the leave-one-out cross-validation method and water as solvent. In particular, the approach presented shapes up as very robust in terms of the evaluated time range under consideration, reflecting well thermodynamic equilibria. These and further observations correlating with experimental results suggest the suitability of the underlying force fields and our multi-mode approach for the estimation of relative binding affinities for host-guest systems with unknown binding modes.

Hands-off Linear Interaction Energy Approach to Binding Mode and Affinity Estimation of Estrogens

“…Charges were assigned with the am1bcc method , approximating restrained electrostatic potential (RESP) charges . As described previously, 60 initial orientations were generated of each ligand’s global minimum conformation sharing the same geometric center which was superimposed with the geometric center of the crystallized E 2 molecule at the binding site. Explicit water solvation was included using Amber’s ffamber_tip3p model which is part of the GAFF–Gromacs MD interface denoted as amber ports .…”

Advances in enantioselective analysis of chiral brominated flame retardants. Current status, limitations and future perspectives

“…3), followed by the γ-enantiomers with (+) γ-eluting ahead of (−) γ -HBCD (Janák et al, 2005). In order to explain this order of elution, (Durmaz et al, 2012), hypothesized that interaction of HBCD enantiomers with β-permethylated cyclodextrin is more likely in water, while enantiomers elution rate is higher in more hydrophobic solvents (i.e. acetonitrile, etc).…”

“…acetonitrile, etc). Using a multi-mode Hamiltonian dynamics simulation model, (Durmaz et al, 2012) calculated the interaction energies of HBCD enantiomers with β-permethylated cyclodextrin and they found that the experimental capacity factors k of enantiomers determined by HPLC are increasing with the absolute value of mean interaction energies of the enantiomers (data taken from (Durmaz et al, 2012) were plotted in Fig. 3).…”

“…This figure was taken from(Koeppen et al, 2007). HBCDspermethylated β-cyclodextrin Interaction Energy (B) as calculated by(Durmaz et al, 2012).…”

Investigation of the Ergopeptide Epimerization Process

“…Afterwards, all geometries were minimized with the conjugate gradient method [13,14] and the lowest energy geometry was chosen as an estimate for the global minimum conformation. As described in Durmaz et al [15], this strategy seems to provide realistic global minima conformations for small molecules. This conformer was then parameterized according to the general Amber force field [16] (GAFF) using Antechamber from the AmberTools v1.4 package [17].…”