Recognition of repulsive and attractive regions of selected serotonin receptor binding site using FMO-EDA approach

Paweł Śliwa,Anna Drabczyk,Rafał Kafel,Jolanta Jaśkowska,Rafał Kurczab

doi:10.1007/s00894-019-3995-6

Abstract

The complexes of selected long-chain arylpiperazines with homology models of 5-HT1A, 5-HT2A, and 5-HT7 receptors were investigated using quantum mechanical methods. The molecular geometries of the ligand–receptor complexes were firstly optimized with the Our own N-layered Integrated molecular Orbital and molecular Mechanics (ONIOM) method. Next, the fragment molecular orbitals method with an energy decomposition analysis scheme (FMO-EDA) was employed to estimate the interaction energies in binding sites. The results clearly showed that orthosteric binding sites of studied serotonin receptors have both attractive and repulsive regions. In the case of 5-HT1A and 5-HT2A two repulsive areas, located in the lower part of the binding pocket, and one large area of attraction engaging many residues at the top of all helices were identified. Additionally, for the 5-HT7 receptor, the third area of destabilization located at the extracellular end of the helix 6 was found.

Highlights

The application of quantum chemical methods for biological systems is usually computationally expensive
Quantum chemical methods were used for the energy characterization of binding sites of 5-HT1A, 5-HT2A, and 5-HT7 receptors
The quality of obtained models can be affected by the template choice or/and options used in the software

Summary

Introduction

The application of quantum chemical methods for biological systems is usually computationally expensive. The fragment molecular orbital method (FMO) [1,2,3] is a convenient tool for calculating the energy of large systems at the ab initio level. The results give additional data that are troublesome to obtain with simple molecular mechanical methods. The FMO method simplified the total energy of a molecule or a molecular cluster divided into N fragments as the following sum:. This paper belongs to Topical Collection 8th conference on Modeling & Design of Molecular Materials (MDMM 2018). Quantum chemical methods were used for the energy characterization of binding sites of 5-HT1A, 5-HT2A, and 5-HT7 receptors. Molecular docking was used to build ligand–receptor complexes of eight long-chain

Methods

Results

Conclusion