Salt Bridge in Ligand–Protein Complexes—Systematic Theoretical and Statistical Investigations

Although the salt bridge is the strongest among all known noncovalent molecular interactions, no comprehensive studies have been conducted to date to examine its role and significance in drug design. Thus, a systematic study of the salt bridge in biological systems is reported herein, with a broad analysis of publicly available data from Protein Data Bank, DrugBank, ChEMBL, and GPCRdb. The results revealed the distance and angular preferences as well as privileged molecular motifs of salt bridges in ligand–receptor complexes, which could be used to design the strongest interactions. Moreover, using quantum chemical calculations at the MP2 level, the energetic, directionality, and spatial variabilities of salt bridges were investigated using simple model systems mimicking salt bridges in a biological environment. Additionally, natural orbitals for chemical valence (NOCV) combined with the extended-transition-state (ETS) bond-energy decomposition method (ETS–NOCV) were analyzed and indicated a strong covale...