Specific interactions between fluorinated vitamin-D3 derivatives and vitamin-D receptor: molecular mechanics and ab initio fragment molecular orbital calculations

The structures of our target VD3 derivatives were optimized using the B3LYP/6-31G(d,p) method of Gaussian 16 (G16). The charge distributions of the optimized structures were calculated by constrained electrostatic potential (RESP) analysis using the HF/6-31G(d) method of G16. The RESP charges were used for describing the electrostatic interactions between each derivative and the VDR residues in classical molecular mechanics (MM) and molecular dynamics (MD) calculations. As the initial structure of VDR, the X-ray crystal structure (PDB ID: 1DB1) was used, and by using the fitting tool (gmx confrms) of the MD simulation program GROMACS, the initial structures of the VDR - derivative complexes were created. To obtain their stable structures, the classical MM method of AMBER18 was used. The tleap command of AMBER18 was employed for adding hydrogen and fluorine atoms to the PDB structure and generating solvation water molecules within 8 Å around the complex. This solvated structure of the complex was optimized using the MM method by considering water molecules explicitly. In the MM optimizations, the AMBER14SB force field, the generalized AMBER force field, and the TIP3P model were assigned for VDR, derivatives, and water molecules, respectively. We furthermore conducted MD simulations (100 ns at 300 K) for the MM optimized structures using the same force fields and confirmed the stability of the complex. Finally, to elucidate the specific interactions between VDR and each VD3 derivative at an electronic level, we investigated the electronic properties of the complexes in explicit water using the ab initio fragment molecular orbital (FMO) method. We employed the ab initio MP2/6-31G(d) method of the FMO calculation program ABINIT-MP Ver6.0, to accurately investigate the π-π stacking, NH-π, and CH-π interactions as well as the hydrogen-bonding and electrostatic interactions between the VDR residues and the derivatives. Furthermore, to highlight the critical VDR residues for the binding between VDR and the derivative, we investigated the inter-fragment interaction energies obtained by the FMO calculations.