Efficient free energy calculations on small molecule host‐guest systems—A combined linear interaction energy/one‐step perturbation approach

Abstract

Two efficient methods to calculate binding affinities of ligands with proteins have been critically evaluated by using sixteen small ligand host-guest complexes. It is shown that both the one-step (OS) perturbation method and the linear interaction energy (LIE) method have complementing strengths and weaknesses and can be optimally combined in a new manner. The OS method has a sound theoretical basis to address the free energy of cavity formation, whereas the LIE approach is more versatile and efficient to calculate the free energy of adding charges to such cavities. The off-term, which is neglected in the original LIE equation, can be calculated without additional costs from the OS, offering a powerful synergy between the two methods. The LIE/OS approach presented here combines the best of two worlds and for the model systems studied here, is more accurate than and as efficient as the original methods. It has a sound theoretical background and no longer requires any empirical parameters. The method appears very well suited for application in lead-optimization programmes in drug research, where the structure and dynamics of a series of molecules is of interest, together with an accurate calculation of the binding free energy.

First principles view on chemical compound space: Gaining rigorous atomistic control of molecular properties

“…[76] Clearly, for the eventual control of ligand binding, the property of interest is not the potential energy of interaction but rather the free energies of binding: solvation or entropic contributions can be crucial, as is well known in general, [77] and in the particular case of ellipticine. [78] For example, Tidor, [79] and Oostenbrink and van Gunsteren [80,81] have carried out similar work in the sense of interpolating ligand candidates, by calculating free energies of binding, and using molecular force fields. For this review, however, we will limit the discussion to the potential energy of interaction.…”

Accelerating equilibrium isotope effect calculations. II. Stochastic implementation of direct estimators

“…Not only do these techniques eliminate the integration error, but they also tend to show faster statistical convergence than does standard thermodynamic integration; 16,20 this property is similar to the improvement achieved by parallel tempering. [21][22][23] The second group is based on the free energy perturbation, 1,15,24,25 which can be derived by rewriting the ratio (2) using the Zwanzig formula; the approach was proposed in Ref. 15, with more convenient estimators introduced in Ref.…”

Saturation Mutagenesis by Efficient Free-Energy Calculation

“… 28 , 37 Still, OSP was repeatedly shown to perform best for nonpolar changes, whereas large changes in polarity lead to poor overlap in the conformational ensembles of the reference state and the end states. 18 , 37 − 39 …”