II. Dissociation free energies in drug-receptor systems via nonequilibrium alchemical simulations

Autor(en)

Francesca Nerattini, Riccardo Chelli, Piero Procacci

Abstrakt

The recently proposed fast switching double annihilation (FS-DAM) [Cardelli et al., J. Chem. Theory Comput., 2015, 11, 423] is aimed at computing the absolute standard dissociation free energies for the chemical equilibrium RL → R + L occurring in solution through molecular dynamics (MD) simulations at the atomistic level. The technique is based on the production of fast nonequilibrium annihilation trajectories of one of the species (the ligand) in the solvated RL complex and in the bulk solvent. As detailed in the companion theoretical paper, the free energies of these two nonequilibrium annihilation processes are recovered by using an unbiased unidirectional estimate derived from the Crooks theorem exploiting the inherent Gaussian nature of the annihilation work. The FS-DAM technique was successfully applied to the evaluation of the dissociation free energy of the complexes of Zn(ii) cations with an inhibitor of the Tumor Necrosis Factor α converting enzyme. Here we apply the technique to a real drug-receptor system, by satisfactorily reproducing the experimental dissociation free energies of FK506-related bulky ligands towards the native FKBP12 enzyme and by predicting the dissociation constants for the same ligands towards the mutant I56D. The effect of such mutations on the binding affinity of FK506-related ligands is relevant for assessing the thermodynamic forces regulating molecular recognition in FKBP12 inhibition.

Organisation(en)

Computergestützte Physik und Physik der Weichen Materie

Externe Organisation(en)

Università degli Studi di Firenze

Journal

Physical Chemistry Chemical Physics

Band

18

Seiten

15005-15018

Anzahl der Seiten

14

ISSN

1463-9076

DOI

https://doi.org/10.1039/c5cp05521k

Publikationsdatum

06-2016

Peer-reviewed

Ja

ÖFOS 2012

106006 Biophysik, 103006 Chemische Physik, 103029 Statistische Physik

Schlagwörter

ASJC Scopus Sachgebiete

Allgemeine Physik und Astronomie, Physical and Theoretical Chemistry

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/0039f0de-1a14-4117-a0fc-316c2901901e