An estimation method of binding free energy in terms of ABEEMσπ/MM and continuum electrostatics fused into LIE method

Abstract

A method is proposed for the estimation of absolute binding free energy of interaction between proteins and ligands. The linear interaction energy method is combined with atom-bond electronegativity equalization method at σπ level Force field (fused into molecular mechanics) and generalized Born continuum model calculation of electrostatic solvation for the estimation of the absolute free energy of binding. The parameters of this method are calibrated by using a training set of 24 HIV-1 protease-inhibitor complexes (PDB entry 1AAQ). A correlation coefficient of 0.93 was obtained with a root mean square deviation of 0.70 kcal mol(-1) . This approach is further tested on seven inhibitor and protease complexes, and it provides small root mean square deviation between the calculated binding free energy and experimental binding free energy without reparametrization. By comparing the radii of gyration and the hydrogen bond distances between ligand and protein of three training model molecules, the consistent comparison result of binding free energy is obtained. It proves that this method of calculating the binding free energy with appropriate structural analysis can be applied to quickly assess new inhibitors of HIV-1 proteases. To test whether the parameters of this method can apply to other drug targets, we have validated this method for the drug target cyclooxygenase-2.

A Large-Scale Test of Free-Energy Simulation Estimates of Protein–Ligand Binding Affinities

“…DHFR was used in a study with the MM/PB­(GB)­SA approach (molecular mechanics with Poisson–Boltzmann or generalized Born and surface-area solvation), and they obtained excellent correlation with experimental data with r 2 > 0.8 for most of their tested protocols . The HIV-PT system has been used in some studies with heavily fitted linear interaction energy models. , Ferritin and fXa have been used in several studies by us, especially when testing the MM/GBSA approach. ,, For CDK2 and fXa, relative binding affinities have been calculated by TI and BAR for other large sets of ligand . For fXa, a decent r 2 = 0.58 but a rather high root-mean-squared error (RMSE) of 9 kJ/mol were obtained.…”

“…All ligands represent pharmaceutical compounds. Most of the systems have been studied with computational tools before, − and all inhibitors bind by noncovalent interactions.…”

Fast and accurate determination of the relative binding affinities of small compounds to HIV-1 protease using non-equilibrium work

“…These computational approaches can be classified in three main group: the fastest prediction can be achieved using the quantitative structure‐activity relationship (QSAR) approach, and the molecular docking simulations; the approximate estimation methods such as the linear interaction energy (LIE), and molecular mechanics‐Poisson‐Boltzmann surface area (MM‐PBSA) . The MM‐PBSA, and the LIE methods have been applied because they provide a good balance between CPU computing consumption and the accuracy desired. In the LIE method, however, the binding free energy is estimated through the equation: , where the and are the different averages of the van der Waals (vdW) and electrostatic interaction energies between the ligand and its environment.…”

Reaction mechanism of NO with hydrolysates of NAMI‐A: an MD simulation by combining the QM/MM(ABEEM) with the MD‐FEP method

“…Wilson and Ichikawa and Torrent‐Sucarrat and coworkers pointed out that the charge transfer between atoms in a molecule is overestimated by using the polarization basis sets. Huzinaka et al, Jakalian et al, Watanabe et al, and our group have shown that the use of higher levels of basis sets overestimates the overlap between their respective basis functions belonging to two atoms in a molecule. Bayly and his coworkers pointed out that when the 6‐31G* basis set is used, the polarity of a molecule calculated by the partial charges is overestimated by 10%–15% .…”