Conformational diversity of the quercetin molecule: a quantum-chemical view

Abstract

This paper focuses on the comprehensive conformational analysis of the quercetin molecule with a broad range of the therapeutic and biological actions. All possible conformers of these molecule, corresponding to the local minima on the potential energy hypersurface, have been obtained by the sequential rotation of its five hydroxyl groups and also by the rotation of its (A?+?C) and B rings relatively each other. Altogether, it was established 48 stable conformers, among which 24 conformers possess planar structure and 24 conformers – nonplanar structure. Their structural, symmetrical, energetical and polar characteristics have been investigated in details. Quantum-mechanical calculations indicate that conformers of the quercetin molecule are polar structures with a dipole moment, which varies within the range from 0.35 to 9.87 Debay for different conformers. Relative Gibbs free energies of these conformers are located within the range from 0.0 to 25.3?kcal·mol^?1 in vacuum under normal conditions. Impact of the continuum with ε?=?4 leads to the decreasing of the Gibbs free energies (–0.19–18.15?kcal·mol^?1) and increasing of the dipole moment (0.57–12.48?D). It was shown that conformers of the quercetin molecule differ from each other by the intramolecular specific contacts (two or three), stabilizing all possible conformers of the molecule – H-bonds (both classical ОН…О and so-called unusual С′Н…О and ОН…С′) and attractive van-der-Waals contacts О…О. Obtained conformational analysis for the quercetin molecule enables to provide deeper understanding of the ‘structure-function’ relationship and also to suggest its mechanisms of the therapeutic and biological actions.

Communicated by Ramaswamy H. Sarma     

Conformational transitions of the quercetin molecule via the rotations of its rings: a comprehensive theoretical study

Abstract

Quercetin is an important flavonoid compound, usually extracted from plants, vegetables and fruits such as blueberries, apples, green tea, wine, onions and possessing broad range of pharmacological properties, in particular, powerful antioxidant, antitoxic, antiinflammation and antimicrobial effects due to its various reactive sites. The structure of this phenolic compound consists of three (A?+?C) and B rings, bearing five hydroxyl groups. Primarily, the chemical structure of quercetin determines its physico-chemical properties. Earlier, it was established that isolated quercetin molecule can acquire 48 stable conformations (24 planar and 24 non-planar) due to the mobility of its hydroxyl groups and (A?+?C) and B rings with relative Gibbs free energies in the range of 0.0–25.3?kcal·mol^?1 under normal conditions (Brovarets’ et al., 2019c Brovarets’, O. O., & Hovorun, D. M. (2019c). Conformational diversity of the quercetin molecule: A quantum-chemical view. Journal of Biomolecular Structure and Dynamics. doi: 10.1080/07391102.2019.1645734[Taylor & Francis Online], [Web of Science ®] , [Google Scholar]). In this work by quantum-mechanical calculations at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of theory and Bader’s ‘Quantum Theory of Atoms in Molecules’, we have theoretically modeled the interconversions in the 24 pairs of the conformers of the quercetin molecule, occuring via the rotation of its non-deformable (A+С) and B rings around the С2-С1' bond through the quasi-orthogonal transition state with low values of the imaginary frequencies (28–33/29–36?cm^?1) and Gibbs free energies of activation in the range of 2.17–5.68/1.86–4.90?kcal·mol^?1 in the continuum with dielectric permittivity ε?=?1/ε?=?4 under normal conditions. Also, we studied the changes of the number of physico-chemical characteristics of all intramolecular-specific contacts – hydrogen bonds and attractive van der Waals contacts during these conformational rearrangements.

Communicated by Ramaswamy H. Sarma     

Investigation of intermolecular interactions and stability of verubecestat in the active site of BACE1: Development of first model from QM/MM-based charge density and MD analysis

Alzheimer disease (AD) is a cruel neurodegenerative disorder caused by the deposition of amyloid β (Aβ) peptide inside the brain. The β-secretase (beta amyloid precursor protein (APP) cleaving enzyme 1, BACE1) is one of the enzymes involved in the cleavage of APP that leads to the Aβ formation and it is the primary target for the treatment of AD. Recent report outlines that verubecestat molecule strongly inhibits BACE1; however, its structure, binding mechanism and the stability in the active site of BACE1 are not yet known. The present study aims to determine the structure, binding affinity and the stability of verubecestat molecule in the active site of BACE1 from the molecular docking, quantum mechanics/molecular mechanics (QM/MM)-based charge density analysis and molecular dynamics simulation. Verubecestat molecule was docked at BACE1; it shows high binding affinity towards BACE1. Further, the conformational geometry and the intermolecular interactions of verubecestat in the active site of BACE1 were determined. The molecule forms strong interaction with the neighboring amino acids in the active site of BACE1. The onsite QM/MM-based charge density analysis reveals the nature of charge density distribution and the topological properties of intermolecular interactions of verubecestat molecule in the active site of BACE1. The calculated electrostatic potential (ESP) of verubecestat in the active site of BACE1 displays high negative and positive ESP regions of the molecule. This onsite QM/MM analysis is more relevant to the physiological situation. The molecular dynamics simulation has been performed, which confirms the high stability and compactness of verubecestat in the active site of BACE1. The MM-generalized Born surface area and MM-Poisson Boltzmann surface area free energy calculations of verubecestat–BACE1 also confirm the high binding affinity of verubecestat.

Communicated by Ramaswamy H. Sarma     

Structural insight for the roles of fas death domain binding to fadd and oligomerization degree of the fas–fadd complex in the death‐inducing signaling complex formation: A computational study

Fas binding to Fas‐associated death domain (FADD) activates FADD–caspase‐8 binding to form death‐inducing signaling complex (DISC) that triggers apoptosis. The Fas–Fas association exists primarily as dimer in the Fas–FADD complex, and the Fas–FADD tetramer complexes have the tendency to form higher order oligomer. The importance of the oligomerized Fas–FADD complex in DISC formation has been confirmed. This study sought to provide structural insight for the roles of Fas death domain (Fas DD) binding to FADD and the oligomerization of Fas DD–FADD complex in activating FADD–procaspase‐8 binding. Results show Fas DD binding to FADD stabilized the FADD conformation, including the increased stability of the critical residues in FADD death effector domain (FADD DED) for FADD–procaspase‐8 binding. Fas DD binding to FADD resulted in the decreased degree of both correlated and anticorrelated motion of the residues in FADD and caused the reversed correlated motion between FADD DED and FADD death domain (FADD DD). The exposure of procaspase‐8 binding residues in FADD that allows FADD to interact with procaspase‐8 was observed with Fas DD binding to FADD. We also observed different degrees of conformational and motion changes of FADD in the Fas DD–FADD complex with different degrees of oligomerization. The increased conformational stability and the decreased degree of correlated motion of the residues in FADD in Fas DD–FADD tetramer complex were observed compared to those in Fas DD–FADD dimer complex. This study provides structural evidence for the roles of Fas DD binding to FADD and the oligomerization degree of Fas DD–FADD complex in DISC formation to signal apoptosis. Proteins 2013. © 2012 Wiley Periodicals, Inc.