Ion-Selective Controlled Assembly of Dendrimer-Based Functional Nanofibers and Their Ionic-Competitive Disassembly

The construction of hierarchical materials through controlled self-assembly of molecular building blocks (e.g., dendrimers) represents a unique opportunity to generate functional nanodevices in a convenient way. Transition-metal compounds are known to be able to interact with cationic dendrimers to generate diverse supramolecular structures, such as nanofibers, with interesting collective properties. In this work, molecular dynamics simulation (MD) demonstrates that acetate ions from dissociated Cd­(CH₃COO)₂ selectively generate cationic PPI-dendrimer functional fibers through hydrophobic modification of the dendrimer’s surface. The hydrophobic aggregation of dendrimers is triggered by the asymmetric nature of the acetate anions (AcO^–) rather than by the precise transition metal (Cd). The assembling directionality is also controlled by the concentration of AcO^– ions in solution. Atomic force (AFM) and transmission electron microscopy (TEM) prove these results. This well-defined directional assembly of cationic dendrimers is absent for different cadmium derivatives (i.e., CdCl₂, CdSO₄) with symmetric anions. Moreover, since the formation of these nanofibers is controlled exclusively by selected anions, fiber disassembly can be consequently triggered via simple ionic competition by NaCl salt. Ions are here reported as a simple and cost-effective tool to drive and control actively the assembly and the disassembly of such functional nanomaterials based on dendrimers

Ion-Selective Controlled Assembly of Dendrimer-Based Functional Nanofibers and Their Ionic-Competitive Disassembly

The construction of hierarchical materials through controlled self-assembly of molecular building blocks (e.g., dendrimers) represents a unique opportunity to generate functional nanodevices in a convenient way. Transition-metal compounds are known to be able to interact with cationic dendrimers to generate diverse supramolecular structures, such as nanofibers, with interesting collective properties. In this work, molecular dynamics simulation (MD) demonstrates that acetate ions from dissociated Cd­(CH₃COO)₂ selectively generate cationic PPI-dendrimer functional fibers through hydrophobic modification of the dendrimer’s surface. The hydrophobic aggregation of dendrimers is triggered by the asymmetric nature of the acetate anions (AcO^–) rather than by the precise transition metal (Cd). The assembling directionality is also controlled by the concentration of AcO^– ions in solution. Atomic force (AFM) and transmission electron microscopy (TEM) prove these results. This well-defined directional assembly of cationic dendrimers is absent for different cadmium derivatives (i.e., CdCl₂, CdSO₄) with symmetric anions. Moreover, since the formation of these nanofibers is controlled exclusively by selected anions, fiber disassembly can be consequently triggered via simple ionic competition by NaCl salt. Ions are here reported as a simple and cost-effective tool to drive and control actively the assembly and the disassembly of such functional nanomaterials based on dendrimers

Free energy landscape of siRNA-polycation complexation: Elucidating the effect of molecular geometry, polymer flexibility, and charge neutralization

<div><p>The success of medical threatments with DNA and silencing interference RNA is strongly related to the design of efficient delivery technologies. Cationic polymers represent an attractive strategy to serve as nucleic-acid carriers with the envisioned advantages of efficient complexation, low cost, ease of production, well-defined size, and low polydispersity index. However, the balance between efficacy and toxicity (safety) of these polymers is a challenge and in need of improvement. With the aim of designing more effective polycationic-based gene carriers, many parameters such as carrier morphology, size, molecular weight, surface chemistry, and flexibility/rigidity ratio need to be taken into consideration. In the present work, the binding mechanism of three cationic polymers (polyarginine, polylysine and polyethyleneimine) to a model siRNA target is computationally investigated at the atomistic level. In order to better understand the polycationic carrier-siRNA interactions, replica exchange molecular dynamic simulations were carried out to provide an exhaustive exploration of all the possible binding sites, taking fully into account the siRNA flexibility together with the presence of explicit solvent and ions. Moreover, well-tempered metadynamics simulations were employed to elucidate how molecular geometry, polycation flexibility, and charge neutralization affect the siRNA-polycations free energy landscape in term of low-energy binding modes and unbinding free energy barriers. Significant differences among polymer binding modes have been detected, revealing the advantageous binding properties of polyarginine and polylysine compared to polyethyleneimine.</p></div

Structure of the siRNA sequence dGdG(AGCAGCACCUUCAGGAU)dUdU and the polycationic polymers investigated in the present work.

<p>Structure of the siRNA sequence dGdG(AGCAGCACCUUCAGGAU)dUdU and the polycationic polymers investigated in the present work.</p

Nucleotides that are mainly responsible for siRNA-polycation interaction have been identified by contact probability plots [71] in case of PEI27, PEI45, polyARG and polyLYS systems.

<p>Nucleotides that are mainly responsible for siRNA-polycation interaction have been identified by contact probability plots [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0186816#pone.0186816.ref071" target="_blank">71</a>] in case of PEI27, PEI45, polyARG and polyLYS systems.</p

Additional file 1: of Thermodynamic and kinetic stability of the Josephin Domain closed arrangement: evidences from replica exchange molecular dynamics

Supporting Information to Thermodynamic and Kinetic Stability of the Josephin Domain Closed Arrangement: Evidences from Replica Exchange Molecular Dynamics. Additional Information on Replica Exchange applied approach, kinetic estimation. (PDF 1183 kb

Distribution plot of the Radius of Gyration (RG) of polyARG, polyLYS, PEI27 and PEI45, respectively.

<p>The computational data were taken from the last 20 ns of the Replica Exchange Molecular Dynamics trajectory at 300K, for each molecular system.</p

Free energy profiles of the JD transition pathway as function of the (a) radius of gyration (RG) and (b) hairpin angle.

<p>The depth of the energy well corresponding to the absolute free energy minimum is highlighted in red. The absolute free energy well is set as zero.</p

Free energy profile (kJ/mol) of siRNA-PEI27 interaction represented as function of siRNA-polycation distance from the major inertia axis of the target siRNA (distance from axis-DFA) and the projection of the siRNA-polymer distance on the major inertia axis of the target siRNA (projection on axis-POA).

<p>The free energy minima computed by metadynamics are compared with the system configurations sampled by REMD simulations (black triangle). The deepest binding site is highlighted with BS1. The visual inspection of each binding site is reported together with the corresponding electrostatic map (right). Potential isocontours are shown at +5kT/e (blue) and -5kT/e (red) and obtained by solution of the LPBE at 150 mM ionic strength with a solute dielectric of 4 and a solvent dielectric of 78.4.</p

Root Mean Square Fluctuation plot.

<p><b>Each point represents the mean fluctuation for each JD residue calculated over the whole MD trajectory (500 ns and five replicas taken together) filtered on the first PCA eigenvector.</b> The hairpin region (Val31-Leu62), composed by helix α2 (dashed red line) and α3 (continuous red line) is highlighted in blue. Secondary structure α6 (Asp145-Glu158) is highlighted in dark green.</p