A Study with Peptide Dendrimers Reveals an Extreme pH Dependence of Antibiotic Activity Above pH 7.4

The presence of ionizable groups in antimicrobial peptides (AMPs) often induces a pH-dependent activity. Herein we report that removing eight low p<i>K</i>_a amino termini in antimicrobial peptide dendrimer (AMPD) <b>G3KL</b> provides dendrimer <b>XC1</b> with a broader pH-activity range. Furthermore, raising the pH to 8.0 reveals strong activities against <i>Klebsiella pneumoniae</i> and methicillin resistant <i>Staphylococcus aureus</i> (MRSA) against which these AMPDs are inactive at pH 7.4. We observe a similar effect with polymyxin B on MRSA. Binding experiments with a fluorescent AMPD and the effect of high salt concentration suggest that the activity increase reflects stronger electrostatic binding to the bacteria at high pH. pH-profiling of other polycationic antimicrobials (polymers, peptidomimetics, foldamers, dendrimers) might similarly enhance their activity range, with possible use for topical treatments.

A Study with Peptide Dendrimers Reveals an Extreme pH Dependence of Antibiotic Activity Above pH 7.4

The presence of ionizable groups in antimicrobial peptides (AMPs) often induces a pH-dependent activity. Herein we report that removing eight low p<i>K</i>_a amino termini in antimicrobial peptide dendrimer (AMPD) <b>G3KL</b> provides dendrimer <b>XC1</b> with a broader pH-activity range. Furthermore, raising the pH to 8.0 reveals strong activities against <i>Klebsiella pneumoniae</i> and methicillin resistant <i>Staphylococcus aureus</i> (MRSA) against which these AMPDs are inactive at pH 7.4. We observe a similar effect with polymyxin B on MRSA. Binding experiments with a fluorescent AMPD and the effect of high salt concentration suggest that the activity increase reflects stronger electrostatic binding to the bacteria at high pH. pH-profiling of other polycationic antimicrobials (polymers, peptidomimetics, foldamers, dendrimers) might similarly enhance their activity range, with possible use for topical treatments.

A Quantum Chemical Topology Picture of Intermolecular Electrostatic Interactions and Charge Penetration Energy

<div>Basing on the Interacting Quantum Atoms approach, we present herein a conceptual and theoretical framework of short-range electrostatic interactions, whose accurate description is still a challenging problem in molecular modeling. For all the non-covalent complexes in the S66 database, the fragment-based and atomic decomposition of the electrostatic binding energies is performed using both the charge density of the dimers and the unrelaxed densities of the monomers. This energy decomposition together with dispersion corrections gives rise to a pairwise approximation to the total binding energy. It also provides energetic descriptors at varying distance that directly address the atomic and molecular electrostatic interactions as described by point-charge or multipole-based potentials. Additionally, we propose a consistent definition of the charge penetration energy within quantum chemical topology, which is mainly characterized in terms of the intramolecular electrostatic energy. Finally, we discuss some practical implications of our results for the design and validation of electrostatic potentials.</div>

A Quantum Chemical Topology Picture of Intermolecular Electrostatic Interactions and Charge Penetration Energy

<div>Basing on the Interacting Quantum Atoms approach, we present herein a conceptual and theoretical framework of short-range electrostatic interactions, whose accurate description is still a challenging problem in molecular modeling. For all the non-covalent complexes in the S66 database, the fragment-based and atomic decomposition of the electrostatic binding energies is performed using both the charge density of the dimers and the unrelaxed densities of the monomers. This energy decomposition together with dispersion corrections gives rise to a pairwise approximation to the total binding energy. It also provides energetic descriptors at varying distance that directly address the atomic and molecular electrostatic interactions as described by point-charge or multipole-based potentials. Additionally, we propose a consistent definition of the charge penetration energy within quantum chemical topology, which is mainly characterized in terms of the intramolecular electrostatic energy. Finally, we discuss some practical implications of our results for the design and validation of electrostatic potentials.</div>

A polybasic domain in aPKC mediates Par6-dependent control of membrane targeting and kinase activity

Mechanisms coupling the atypical PKC (aPKC) kinase activity to its subcellular localization are essential for cell polarization. Unlike other members of the PKC family, aPKC has no well-defined plasma membrane (PM) or calcium binding domains, leading to the assumption that its subcellular localization relies exclusively on protein–protein interactions. Here we show that in both Drosophila and mammalian cells, the pseudosubstrate region (PSr) of aPKC acts as a polybasic domain capable of targeting aPKC to the PM via electrostatic binding to PM PI4P and PI(4,5)P2. However, physical interaction between aPKC and Par-6 is required for the PM-targeting of aPKC, likely by allosterically exposing the PSr to bind PM. Binding of Par-6 also inhibits aPKC kinase activity, and such inhibition can be relieved through Par-6 interaction with apical polarity protein Crumbs. Our data suggest a potential mechanism in which allosteric regulation of polybasic PSr by Par-6 couples the control of both aPKC subcellular localization and spatial activation of its kinase activity.