Effect of Peptide Charge Distribution on the Structure and Kinetics of DNA Complex

Abstract

The complexes formed by DNA or siRNA interacting with polycations showed great potential as nonviral vectors for gene delivery. The physicochemical properties of the DNA/siRNA complexes, which could be tuned by adjusting the characteristics of polycations, were directly related to their performance in gene delivery. Using 21 bp double-stranded oligonucleotide (ds-oligo) and two icosapeptides (with the repeating units being KKGG and KGKG, respectively) of the same charge density as model molecules, we investigated the effect of charge distribution on the kinetics of complexation and the structure of the final complexes. Even though the distribution of the charged groups in peptides was only adjusted by one position, the complexes formed by (KKGG) 5 and ds-oligo were larger in size and easier to precipitate than those formed by (KGKG) 5 . Counterintuitively, it was not the charged groups but the hydrophilic neutral spacers that determined the kinetics and the structure of the complex. We attributed such an effect to the water-mediated disproportionation process. The hydrophilic spacers next to each other were better than that in the separated pattern in holding water molecules after forming the complex. The water-rich domains in the complex functioned as a lubricant and facilitated the relaxation of the polyelectrolyte, resulting in a fast complexation process. The resulting complex was thus larger in size and lower in surface energy.

Nucleic Acids Based Polyelectrolyte Complexes: Their Complexation Mechanism, Morphology, and Stability

“…The transfection of nucleic acids into cells requires the use of proper vectors for delivery. − While a number of viral gene vectors have been developed, they have the common adverse effect of inducing immune responses in organisms. − To design nonviral gene vectors, new materials are needed that can interact with nucleic acids to form complexes of suitable size and surface charge for transfection across the cell membrane. − Additionally, the complexed nucleic acids need to preserve their sequence information and at the same time be protected from enzymatic digestions in cells. ,− One group of materials that are considered as attractive candidates is made up of cationic surfactant and homopolymer. When they are mixed with long dsDNA, they can efficiently condense DNA leading to the formation of polyelectrolyte complexes (polyplexes) of varied morphologies. ,− For this system, factors including complex size, surface charge, and long-term stability are closely related to gene delivery efficiency, and they have been extensively investigated by both experimental and theoretical studies. ,− In recent years, block copolymers as gene vectors have received increasing attention. When block copolymers containing one cationic block and one neutral block are mixed with nucleic acids, nanosized polyelectrolyte complex micelles (PCMs) are formed. − The cationic block interacts with the nucleic acids and contributes to their condensation.…”

Bulk and nanoscale polypeptide based polyelectrolyte complexes

“…[46] In addition, synthetic parameters like chemical composition, chain length, charge density and topology can be easily tuned to modulate complexation kinetics and ultimately the final polyplex structure. [47] The physiochemical properties of peptide based polyplexes ( e.g. , size, surface charge, interaction strength, colloidal stability) may also be altered via preparation conditions, including ionic strength, pH, concentration, solvent quality, and mixing order.…”

“…, size, surface charge, interaction strength, colloidal stability) may also be altered via preparation conditions, including ionic strength, pH, concentration, solvent quality, and mixing order. [47] To overcome the aforementioned extra- and intracellular barriers, specific classes of peptides are integrated into polyplex delivery vectors, including nucleic acid complexation peptides (high lysine and arginine content), cell-penetrating peptides (CPPs), membrane perturbing peptides and peptides containing nuclear localization sequences (NLSs). [46] However, the physiochemical properties of polyplexes, including phase behavior, and their effects on nucleic acid delivery are still not well understood.…”

Self‐assembly of hairpin peptides mediated by Cu(II) ion: Effect of amino acid sequence

“…[25,26] The charge distribution in molecules could also affect molecular self-assembly and further the function of self-assemblies when peptides contained charged amino acids. [27][28][29][30][31] In addition, the hydrophobic amino acid residues in peptide sequence could also affect the self-assembled supramolecular nanostructures. [32,33] Isoleucine residue away from alkyl tail facilitated the fiber formation and changed the pH value of self-assembly morphology transition.…”