Insights into the structure-affinity relationships and solvation effects between OfHex1 and inhibitors using molecular dynamics simulations.

OfHex1 is a potential target for the rational design of pesticides. TMG-chitotriomycin is one of the most highly specific known inhibitors of chitinolytic β-GlcNAcases from bacteria, fungi and insects. TMG-chitotriomycin and its analogues show different activities to OfHex1, dependent on the number of GlcNAc units. Subsequently, it is essential to explore how these GlcNAc unit number changes cause alterations in activity. In this study, we examined the free energy patterns and per residue decomposition of binding within the complexes of OfHex1 and a series of inhibitors, utilizing restricted molecular dynamics (MD) and water-mediated MM/GBSA calculations. The results indicated Glu328 could form a stronger polar interaction with OfHex1 inhibitors, while Trp448 and Trp490 had important non-polar contributions. Interestingly, the conformation of Trp448 was different in the open or closed state, when OfHex1 bound different inhibitors. Moreover, the water molecule that mediates the GlcNAc Ⅱ and Trp490 may be critical to stabilizing the hydrophobic interaction. Further study showed that isomerization of TMG-chitotriomycin analogs did not decrease binding affinity, however, there was a highly positive correlation between the calculated binding affinities and the experimental activity data (r2  = 0.92) when water molecules were explicitly taken into account. Moreover, the water molecules that mediated GlcNAc II and Trp490 might be critical to the stabilization of the hydrophobic interaction and cause the activity difference between TMG-(GlcNAc)2 and TMG-(GlcNAc).