Understanding the hydrogen bonding preferences and dynamics of prontosil in water and methanol

Solvation energy, defined as the Gibbs energy change accompanying the transfer of a molecule or an atom from vacuum to the solution, plays a crucial role in understanding molecular interactions. In this study, we explore the interaction of prontosil, an important sulfa drug and the first developed antibiotic capable of combating grampositive cocci bacteria with two common solvents, methanol and water. To investigate these interactions, we employed the DFT/M06-2X/cc-pVDZ level of theory for the geometry optimization of each system. Considering prontosil's six electronegative sites that offers numerous possibilities for interactions, we observed prominent interactions between the drug prontosil and the solvents water and methanol at various sites. The prontosil-water and prontosil-methanol complexes most stable sites were used for additional research. The NBO analysis provided insights into the delocalization phenomena present in prontosil under vacuum and in the presence of solvents. The non-covalent interactions (NCI) and reduced density gradient (RDG) plot aided in the interpretation of the steric interactions, strong and weak hydrogen bonds, as well as intra and intermolecular interactions within prontosil and its complexes. In the NBO analysis, the hydrogen and electronegative atoms of the most stable site of the prontosil-methanol complex showed the highest transmittance energy and in the case of the NCI plot, the same region displayed a blue colour which denotes a strong hydrogen bond. After calculating the quantum chemical parameters of reactivity, it was observed that the prontosil-methanol complex had a lower electrophilicity and is hence more stable. Quantum theory of atoms in molecules (QTAIM) analysis revealed the existence of non-covalent interactions at all the bond critical points (BCP) under consideration in the prontosil molecule and its complexes formed with the solvents. Further investigation of several QTAIM parameters revealed that the prontosil-methanol complex exhibited the lowest binding energy, indicating the most stable interactions among the investigated bond critical points. Additionally, we employed local energy decomposition (LED) and ab initio molecular dynamics (AIMD) simulations based on the M06-2X/cc-pVDZ method, with LED analysis performed using DLPNO-CCSD(T). The LED analysis demonstrated that prontosil exhibits more pronounced interactions with methanol than water, and we explored how energy distributions contribute to the total binding energy. Prontosil-methanol complex showed the lowest energy (-14.50 kcal/mol) than the prontosilwater complex (-14.32 kcal/mol). The LED analysis provided insights into why the total binding energy is attractive and predominates the repulsive nature. AIMD simulations of prontosil-methanol complexes yielded favourable results when compared to prontosil-water complexes.