Theoretical studies of the solvent effect on conformational equilibria and atomic charges for isolated and hydrogen-bonded dimethoxy thiadiazoles

Thiadiazoles and their dimethoxy derivatives are substructure motifs for specific muscarinic agonist ligands under development in this laboratory. The B3LYP/aug-cc-pvtz and MP2/aug-cc-pvtz optimized geometric parameters for the four isomeric thiadiazole rings were close to the experimental values in the gas phase. Relative free energies were calculated for 11 conformers of the isomeric dimethoxy thiadiazoles in the gas phase, in tetrahydrofuran, and water solvent. In-solution calculations were performed using the IEF-PCM polarizable continuum method at the B3LYP/6-31G∗ and B3LYP/aug-cc-pvtz levels. In aqueous solution, a main conformation with at least 95% of the total population was calculated for each of the dimethoxy-1,2,3- and 1,2,5-thiadiazoles, whereas a second conformation with populations of 14–18% was predicted to be present in aqueous solution for the 1,2,4- and 1,3,4-thiadiazole derivatives. Net atomic charges obtained by the CHELPG fit to the in-solution molecular electrostatic potential indicated only a moderate solvent effect on the derived values. The IEF-PCM/B3LYP/6-31G∗-derived charges provide a reasonable alternative to those from IEF-PCM/B3LYP/aug-cc-pvtz calculations and could be applied in molecular dynamics and Monte Carlo simulations for thiadiazole ligand – receptor complexes. Consideration of the charge transfer for hydrogen-bonded complexes of the dimethoxy 1,2,4-thiadiazole and amino acid side-chain mimics is, however, a key issue throughout MC/FEP calculations. The applied charge sets affect the calculated binding constant by a factor up to 40–80 at T = 310 K. A re-parameterization for the amino acid residues has been suggested in such cases so that the ligand + amino acid residue maintain together an integer value net charge.