Investigating effects of bridging water on the binding of neuraminidase−ligands using computational alanine scanning combined with interaction entropy method

Abstract Bridging water can form hydrogen bonds with protein and ligand, thus it plays an important role in the binding of protein and ligand. However, the detailed binding mechanism between bridging water and protein−ligand complexes is still unclear. In this study, the effect of bridging water on the binding of neuraminidase (NA) and two ligands (G20 and G28) was investigated using molecular dynamic (MD) simulations and computational alanine scanning combined with the newly developed interaction entropy method. The calculated binding free energy was consistent with the experimental value. Moreover, the rank of calculated binding free energy was in excellent agreement with the experimental rank. Computation analysis showed that the addition of bridging water was beneficial to the binding of NA and ligand, and remarkably enhanced the binding free energy. This is because the existence of bridging water leads to the enhancement in the energy of some residues. Therefore, the number of hot-spot residues also increases after considering bridging water. Our study identified that Leu134, Asp151, Arg152, Trp178, Ile222, Arg224, Glu227, Glu276, Glu277, Arg292 and Tyr406 were the key residues in the neuraminidase−ligand complex. Besides, hydrogen bond analysis showed that bridging water could regulate the hydrogen bond network, and thus could increase the number of hydrogen bonds. It is helpful for enhancing the stability of the complex and is one of the reasons for promoting their binding. These results provide directions and ideas for the design of more effective drugs against neuraminidase in the future.