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Structuring Peptide Dendrimers through pH Modulation and Substrate Binding.

Authors
  • Filipe, Luís C S1
  • Campos, Sara R R1
  • Machuqueiro, Miguel2
  • Darbre, Tamis3
  • Baptista, António M1
  • Sara Campos
Type
Published Article
Journal
The Journal of Physical Chemistry B
Publisher
American Chemical Society
Publication Date
Sep 28, 2016
Volume
120
Issue
38
Pages
10138–10152
Identifiers
DOI: 10.1021/acs.jpcb.6b05905
PMID: 27588342
Source
Medline
Language
English
License
Unknown

Abstract

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.

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