Centro de Química e Bioquímica and Departamento de Química e B...

Dendrimers are a family of ramified synthetic molecules pH effects and electrostatic interactions are known to be crucial players to explain the conformational and functional behaviors observed in these systems Nonetheless to date no computational study involving these systems has explicitly addressed the protonation equilibrium taking place at different pH values for dendrimers containing multiple ionizable sites Herein we present the results of constant-pH molecular dynamics simulations performed at several pH values for four peptide dendrimers of different generations from one to four composed of the same type of amino acids histidines serines and diaminopropionic acid These dendrimers are known to catalyze the hydrolysis of pyrene sulfonate esters Constant-pH MD simulations in the presence of substrate molecules at the optimum pH for catalysis are also reported The results show that first and second generation dendrimers are almost structurally unresponsive to pH variations For third and fourth generation dendrimers pH plays a structuring role with markedly different behaviors being observed when passing from acidic to neutral pH Protonation-conformation coupling effects influence several intramolecular interactions which in turn modulate the shape and structure at the different pH values The atypical and highly pH-dependent protonation profiles of some histidine residues are also investigated The interactions between dendrimers and substrates restrict the conformational space available to the dendrimers and enforce conformational homogeneity This structuring effect is a consequence of the dendrimer-substrate interactions which occur through stabilizing hydrogen bonds and ion pairs between the substrate sulfonate groups and the dendrimer residues Our results provide original fundamental data contributing to the development of novel pH-modulated dendritic systems and the improvement of the existing ones

Centro de Química e Bioquímica and Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa , 1749-016 Lisboa, Portugal.

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Structuring Peptide Dendrimers through pH Modulation and Substrate Binding.