Synergy of Intramolecular Hydrogen-Bonding Network in myo-Inositol 2-Monophosphate:  Theoretical Investigations into the Electronic Structure, Proton Transfer, and pKa

This work demonstrates the pivotal role that an intramolecular hydrogen-bonding network (intra-HBN) plays in the determination of the conformation of myo-inositol 2-monophosphate (Ins(2)P1), a member of the inositol phosphate family of compounds, which are important participants in the role that phosphates play in biological and environmental chemistry. For biologically significant compounds that contain phosphate and hydroxyl groups, Ins(2)P1 is a model system for studying both the primary forces that determine their conformations and their chemical properties from the effect of phosphate group addition. We performed ab initio calculations to determine the intra-HBN within important thermally accessible conformations for neutral Ins(2)P1 and its anions, Ins(2)P1(1-) and Ins(2)P1(2-). The results show that the global minima prefer 1a/5e structures where the phosphate group is in the axial position with all -OH groups in the equatorial positions. The calculations of transition state structures for ring inversion at each ionization state predict an activation energy of 18.16 kcal/mol for the neutral species in water, while the activation energy is lower for the charged compounds, 15.62 kcal/mol for Ins(2)P1(1-) and 12.48 kcal/mol for Ins(2)P1(2-). The pK(a) values of Ins(2)P1 were calculated by modeling the solvent as a polarizable continuum medium (PCM) and as explicit solvent molecules. These values are in good agreement with experimental data. A novel four-center pattern of hydrogen bonding was found to stabilize the system. The intramolecular proton transfer across a low barrier hydrogen bond between the charged phosphate and hydroxyl groups was found to occur under standard conditions with an activation energy that is less than 0.5 kcal/mol.