Computational approaches such as docking and classical molec

Computational approaches such as docking and classical molecular dynamics (MD) are now commonly used to study the structure and dynamics of proteins as well as associated protein-ligand interactions [12]. A fundamental requirement of MD in order to accurately determine the behavior of a protein over time is a correct set of potential energy functions commonly referred to as a force field [13]. The majority of existing force fields can be adequately used to study the structural and mechanistic details of proteins without the presence of non-protein entities such as cofactors or ligands. However, for metalloproteins, these pairwise-additive force fields cannot be applied due to their inability to handle polarization and ligand metal charge transfer effects [14]. A commonly used method to study metalloenzymes is the quantum mechanical (QM) approach where the 8-CPT-Cyclic AMP sodium salt sale structure of atoms is accounted for explicitly at each step during simulation [15], [16], [17]. However, this cannot be used for large systems of more than 100 atoms due to the expense of this computational approach. To overcome this limitation, combined QM and molecular mechanics (MM) approaches are used, where the QM may be at the density functional theory (DFT) level. Currently, correct force field parameters describing the IN-Mg2+ coordination geometry are limited, hence restricting the use of MD in the evaluation of these enzyme-ligand interactions. In the literature, Nuclear Magnetic Resonance (NMR) type restraints have been used to describe IN-Mg coordination [18]. As this approach does not take into consideration the dihedrals and bond angles in the active site, a more accurate description of IN-Mg2+ is required. In this study, force field parameters for HIV-IN CCD active site were computed through QM-based potential energy surface (PES) scans. Obtained parameters were then validated via MD simulations involving the protein in complex with the ligand Raltegravir, within an aqueous environment. This work presents new force field parameters that can be used in computational approaches that study the interactions between CCD and potential HIV-INSTIs.
Methodology
Results and discussion
Conclusions With QM, PES scans were used to elucidate the bond stretch, angle bend and torsions CHARMM force field parameters of the Mg2+ active site of HIV-IN CCD. To decrease the computational cost associated with these calculations a subset of active site residues was used to perform the calculations. Both the PES scans and the RESP atomic charge calculations were performed at the B3LYP level of theory using the LanL2DZ for the Mg2+ and the 6-31G for all other atoms. The force field parameters were successfully validated using MD simulations. It was found that these force field parameters were adequate in describing apo protein dynamics as well as protein-ligand interactions during simulations involving the CCD of HIV-IN. As a result, these force field parameters can be used in anti-HIV-IN drug discovery studies using computational approaches.
Acknowledgements TM acknowledges Rhodes University Research Office for postdoctoral fellowship. Authors acknowledge use of Centre for High Performance Computing (CHPC), South Africa.
Introduction For centuries, medicinal plants have been used in folklore medicine to treat various human diseases [1]. Recently, there has been a growing interest in the therapeutic value of unconventional and underutilized herbal plants considered to be wild plants or weeds [[2], [3], [4]]. These vegetables contain high levels of secondary metabolites, such as hydroxycinnamic acids (HCAs), flavonoids, and alkaloids [4]. The most commonly occurring HCA derivatives include caffeoylquinic acid, feruloylquinic acid, p-coumaroylquinic acid and chicoric acids [[5], [6], [7]]. Chicoric acid (CA) has previously been reported to possess significant medicinal properties, such as anti-bacterial [8], antioxidant [9,10], anti-diabetic [8] and antiviral properties [11].