Molecular dynamics study of quercetin and some of its succinyl derivatives in aqueous solution

Abstract

Introduction. Numerous and diverse biological activity of flavonoid quercetin motivates interest to the peculiarities of its structure as a prerequisite for understanding its structure-function properties which are not fully understood today and remain an object of physico-chemical, biological and structural studies. In the solid state, quercetin is known to exist in two crystal forms, quercetin monohydrate and quercetin dihydrate. But there are only scare data on its structure in the aqueous solution. High-throughput screening studies indicated that quercetin belongs to promiscuous inhibitors and is hypothesized to form aggregates comprising of many individual molecules. To investigate the peculiarities of structure and intermolecular interactions of quercetin as well as some of its succinyl derivatives in liqiud phase we carried out molecular dynamics simulation of their behavior in the aqueous solution.  Methods . Molecular dynamics simulations and the data analysis were performed by molecular modeling program YASARA Structure. Molecules of quercetin or its succinyl derivatives were randomly placed within a dodecahedral simulation cell. Simulation cell was filled with TIP3P water molecules to reach 10 % concentration of quercetin or its succinyl derivatives. Na+ and Cl¯ counterions were added to neutralize the system and to reach ion mass fraction 0.9% NaCl. The molecular system was energy-minimized using AMBER14 force field with 8 Ǻ force cutoff for dispersion interactions. To treat long-range electrostatic interactions the Particle Mesh Ewald algorithm was used. After a short steepest descent minimization, the procedure continued by simulated annealing minimization. The molecular dynamics simulations were run in NPT ensemble at 300 K and pH 7.4 using a multiple timestep of 2.5 fs for intra-molecular and 5 fs for inter-molecular forces. For each molecular system, trajectories were computed for 100 ns. Results and discussion. From the first nanoseconds of simulations, molecules of quercetin as well as succinyl-quiercetins approached one another and began to self-organize into a compact aggregate that remained stable during further simulation time. Driving forces of the aggregate formation were the hydrophobic stacking interactions between aromatic systems of neighbor molecules. Due to a bulky succinyl substituent the aromatic systems of neighbor succinyl-quercetin molecules could not overlap optimally to ensure efficient stacking interactions that resulted in the higher mobility of the molecules in the aggregate and the possibility to form easily intermolecular H-bonds. Behavior of completely succinylated quercetin, 3,4´,5,5´,7-succinyl quercetin, in aqueous solution was essentially different. In this case, molecules remained free the majority of time and sometimes formed short-lived complexes between two or three molecules. The driving forces of the complex formation are hydrophobic and ionic intermolecular interactions. Hydrophobic interactions occurred between aliphatic residues, between aliphatic residues and aromatic systems, and also between aromatic systems. The later took place in T-shape ring arrangement. Ionic interactions between molecules of completely succinylated quercetin are mediated by their interactions with one or two Na+ ions. Conclusions. Results of our molecular dynamics simulations of the behavior of quercetin and some of its succinyl derivatives in aqueous solution are in line with the hypothesis of the self-organized aggregate formation by molecules of promiscuous inhibitor quercetin and reveal the peculiarities of the structure and intermolecular interactions within the aggregates in case of quercetin and the combinatorial mixture of its succinyl derivatives. These data may be useful for the search of new drugs based on quercetin as a lead compound.