Exploring the dominant interactions: unveiling the stable structure of theobromine-water complexes through DFT and ab...

Solute-solvent interactions are crucial for life processes, as biological reactions primarily take place in liquid environments. Water, owing to its remarkable capacity for hydrogen bonding, plays a pivotal role as a solvent in these biological systems. This study computationally investigates the hydration of theobromine, a molecule with significant therapeutic potential and a favorable safety profile. It focuses on the intermolecular interactions within 1:1 theobromine-water complexes in order to provide a comprehensive identification of the potential interaction sites for water when theobromine is dissolved in it. In addition, the research extends to investigate species with up to three water molecules to explore the potential for cooperative binding phenomena.

In this work, we have employed MP2/6-311++G(d,p) and $$ B97XD/6-311++G(d,p) levels of theory within Gaussian09 to optimize geometries and calculate the energies of theobromine-water complexes. Eight stationary points have been identified on the 1:1 theobromine-water potential energy surface, with the majority exhibiting dual hydrogen bond motifs and deviations from linearity. The global minimum structure is characterized by the simultaneous presence of O-H-O and N-H-O hydrogen bonds, with interaction energies of 7.78 kcal/mol and 9.29 kcal/mol determined at the MP2/6-311++G(d,p) and $$ B97XD/6-311++G(d,p) levels of theory, respectively. Natural bond orbital (NBO) analysis at the MP2/6-311++G(d,p) level has been used to quantify donor-acceptor charges and hyperconjugation energies. A linear correlation between interaction energy, charge density, and bond length elongation has been observed, highlighting the intricate interplay of these key parameters. To investigate cooperative hydrogen bonding, we have modeled complexes with up to three water molecules. Weak interactions have been further characterized using atoms in molecules (AIM) analysis and reduced density gradient (RDG) approach. We have found that increasing the hydration up to two water molecules significantly reduces the tautomerization barrier from 46.09 to 20.47 kcal/mol.