Affinity Calculations of Cyclodextrin Host-Guest Complexes: Assessment of Strengths and Weaknesses of End-Point Free Energy Methods.

Research paper by Dimas D Suarez, Natalia N Diaz

Indexed on: 20 Dec '18Published on: 20 Dec '18Published in: Journal of Chemical Information and Modeling


The end-point methods like MM/PBSA or MM/GBSA estimate the free energy of a biomolecule by combining its molecular mechanics energy with solvation free energy and entropy terms. Their performance largely depends on the particular system of interest and despite numerous attempts to improve their reliability that have resulted in many variants, there is still no clear alternative to improve their accuracy. On the other hand, the relatively small cyclodextrin host-guest complexes, for which high quality binding calorimetric data are usually available, are becoming reference models for testing the accuracy of free energy methods. In this work, we further assess the performance of various MM/PBSA-like approaches as applied to cyclodextrin complexes. To this end, we select a set of complexes between β-CD and 57 small organic molecules that has been previously studied with the binding energy distribution analysis method in combination with an implicit solvent model (JCTC, 2013, 9, 3136). For each complex, a conventional 1.0 s MD simulation in explicit solvent is carried out. Then we employ semiempirical quantum chemical calculations, several variants of the MM-PB(GB)SA methods, entropy estimations, etc., in order to assess the reliability of the end-point affinity calculations. The best end-point protocol in this study, which combines DFTB3 energies with entropy corrections, yields estimations of the binding free energies that still have substantial errors (RMSE=2.2 kcal/mol), but exhibits a good prediction capacity in terms of ligand ranking (R2=0.66) that is close or even better than that of rigorous free energy methodologies. Our results can be helpful to discriminate between the intrinsic limitations of the end-point methods and other sources of error, such as the underlying energy and continuum solvation methods.