Preferred microenvironments of halogen bonds and hydrogen bonds revealed using statistics and QM/MM calculation...

Hydrogen bonds (HBs) and halogen bonds (XBs) are two essential non-covalent interactions for molecular recognition and drug design. As proteins are heterogeneous in structure, the microenvironments of protein structures should have effects on the formation of HBs and XBs with ligands. However, there are no systematic studies reported on this effect to date. For quantitatively describing protein microenvironments, we defined the local hydrophobicities (LHs) and local dielectric constants (LDCs) in this study. With the defined parameters, we conducted an elaborate database survey on the basis of 22 011 ligand-protein structures to explore the microenvironmental preference of HBs (91 966 in total) and XBs (1436 in total). The statistics show that XBs prefer hydrophobic microenvironments compared to HBs. The polar residues like ASP are more likely to form HBs with ligands, while nonpolar residues such as PHE and MET prefer XBs. Both the LHs and LDCs (10.69 ± 4.36 for HBs; 8.86 ± 4.00 for XBs) demonstrate that XBs are prone to hydrophobic microenvironments compared with HBs with significant differences (p < 0.001), indicating that evaluating their strengths in the corresponding environments should be necessary. Quantum Mechanics-Molecular Mechanics (QM/MM) calculations reveal that in comparison with vacuum environments, the interaction energies of HBs and XBs are decreased to varying degrees given different microenvironments. In addition, the strengths of HBs are impaired more than those of XBs when the local dielectric constant's difference between the XB microenvironments and the HB microenvironments is large.