Binding Analysis of Some Classical Acetylcholinesterase Inhibitors: Insights for a Rational Design Using Free Energy Perturbation Method Calculations with QM/MM MD Simulations

Abstract

In the present study, the binding free energy of some classical inhibitors (DMT, DNP, GNT, HUP, THA) with acetylcholinesterase (AChE) is calculated by means of the free energy perturbation (FEP) method based on hybrid quantum mechanics and molecular mechanics (QM/MM) potentials. The results highlight the key role of the van der Waals interaction for the inhibition process, since the contribution of this term to the binding free energy is almost as decisive as the electrostatic one. The analysis of the geometrical parameters and the interaction energy per residue along the QM/MM molecular dynamics (MD) simulations highlights the most relevant interactions in the different AChE-ligand systems, showing that the charged residues with a more prominent contribution to the interaction energy are Asp72 and Glu199, although the relative importance depends on the molecular size of the ligand. A correlation between the binding free energy and the number of cation-π interactions present in the systems has been established, DMT being the most potent inhibitor, capable of forming four cation-π interactions. A layer of water molecules surrounding the inhibitors has been observed, which act as bridges along a network formed by the ligands and the residues of the gorge and also between different residues. Although several hydrogen bonds between ligands and AChE do appear, no significant values of BIEs have been recorded. This behavior can be accounted for by the special features of AChE, such as the presence of several subsites of different natures in the gorge or the existence of several water molecules that act as bridges in the electrostatic interactions.

Binding free energy calculations to rationalize the interactions of huprines with acetylcholinesterase

“…Unfortunately, the methods with less computational cost were not always able to reproduce the experimental results [18]. Recently, we have published a paper where the binding free energy of some classical inhibitors of AChE was calculated, obtaining good results with an acceptable computational cost [22]. In that work, the ligands that were studied had quite different protein affinities.…”

Quantum Chemical Approaches in Structure-Based Virtual Screening and Lead Optimization

“…The binding process of five classical AChE inhibitors was analyzed using free energy perturbation (FEP) and QM/MM MD simulations (Nascimento et al, 2017 ). The QM calculations were performed at the AM1 level.…”

A protein interaction free energy model based on amino acid residue contributions: Assessment of point mutation stability of T4 lysozyme

“…Experimental measures of thermal stability (ΔΔG exp ) do not reveal which state or states are perturbed by mutation. Theoretical appraisal of thermal stability does not require knowledge of which states are perturbed, provided the energetics of a suitably representative set of a very large number of conformational microstates are computed accurately across appropriate timescales [45][46][47] . This is difficult to achieve with certainty.…”

“…For example, in drug discovery, small molecule-protein binding free energy is sometimes rationalized in terms of individual interactions between the small molecule and the protein 62 . Recent studies based on sound theories use all-atom simulations to estimate free energy 15,16,47,63 . These computed free energies are not decomposed into individual interactions, even in cases where free energy is binned on a per-residue basis 20,64,65 , are determined by thermodynamic cycles that swap solvent arrays 14,[66][67][68] , or dissected in terms of many-body correlated changes 60,61 .…”