Micro-solvation of a bisphosphonate group: an ab initio and effective fragment potential analysis

Bisphosphonates are very important in diagnosis and treatment of many diseases related to bone. These compounds are soluble in water and have complex hydrogen bond patterns. To investigate the role of H-bonding in their stability, conformational space of two protonation states of methylene bisphosphonate (MBP) and 1-hydroxyethylidene-1,1-diphosphonate (HEDP) in aqueous medium were studied using ab initio calculations, with focus on the ability of effective fragment potential (EFP) to represent the solvent effect. Monte-Carlo global minimum search which performed in this study resulted in 2, 6, 9, and 27micro-solvated structures for MBP-HL, MBP-H2L, HEDP-HL, and HEDP-H2L, respectively. The most stable structures and their equilibrium populations were analyzed at two protonation states and both inter- and intra-molecular H-bond patterns were determined by using geometrical criteria. In comparison with previous studies that have been performed in implicit solvent medium, it was shown that the explicit solvent-solute interactions will change the relative stability and population of different conformers. However, the intra-molecular H-bonds are still more determinative in stability of different conformers in comparison with inter-molecular ones.