Molecular dynamics and docking studies of single site esterase peptide dendrimers

Herein we report the first molecular dynamics and docking study of peptide dendrimers, at the example of dendrimers catalyzing the hydrolysis of acyloxy pyrene trisulfonates in aqueous buffer. Molecular dynamics provide models comparable to the observation by diffusion-NMR showing that the dendrimers exist as conformationally flexible molten globules in aqueous solution. Packing is evidenced by the occurrence of close contacts between topologically distant amino acids in the dendrimer model. Backbone hydrogen bonds predominantly form 2, 3, or 4 residues apart as found in the secondary structures of proteins, however, with lower frequency. The catalytic residues are present at the surface of the dendrimer model at relative positions compatible with binding and esterolysis. Docking of the substrate to low-energy conformations of the dendrimers predicts the formation of dendrimer-substrate complexes with one or two salt bridges between the sulfonate and protonated arginine or histidine residues. Substrate binding in the docked models also involves 4-6 van der Waals contacts. In the catalytic dendrimers RG3 and RMG3 exhibiting a positive dendritic effect, these docking contacts involve the outer dendritic branches. By contrast, in the catalytic dendrimers HG3 or HMG3 where no such effect occurs, the docking contacts are concentrated at the dendritic core. The present investigations provide an unprecedented insight into the molecular dynamics of peptide dendrimers that may be of general significance for other conformationally flexible dendrimers.