Molecular Dynamics Simulations of Polyelectrolyte Complexes

Polyelectrolyte complexes (PECs) are currently of great interest due to their applications toward developing new adaptive materials and their relevance in membraneless organelles. These complexes emerge during phase separation when oppositely charged polymers are mixed in aqueous media. Peptide-based PECs are particularly useful toward developing new drug delivery methods due to their inherent biocompatibility. The underlying peptide sequence can be tuned to optimize specific material properties of the complex, such as interfacial tension and viscosity. Given their applicability, it would be advantageous to understand the underlying sequence-dependent phase behavior of oppositely charged peptides. Here, we report microsecond molecular dynamic simulations to characterize the effect of hydrophobicity on the sequence-dependent peptide conformation for model polypeptide sequences that were previously reported by Tabandeh et al. These sequences are designed with alternating chirality of the peptide backbone. We present microsecond simulations of six oppositely charged peptide pairs, characterizing the sequence-dependent effect on peptide size, degree of hydrogen bonding, secondary structure, and conformation. This analysis recapitulates sensible trends in peptide conformation and degree of hydrogen bonding, consistent with experimentally reported results. Ramachandran plots reveal that backbone conformation at the single amino acid level is highly influenced by the neighboring sequence in the chain. These results give insight into how subtle changes in hydrophobic side chain size and chirality influence the strength of hydrogen bonding between the chains and, ultimately, the secondary structure. Furthermore, principal component analysis reveals that the minimum energy structures may be subtly modulated by the underlying sequence

Oligonucleotide–Peptide Complexes: Phase Control by Hybridization

When oppositely charged polymers are mixed, counterion release drives phase separation; understanding this process is a key unsolved problem in polymer science and biophysical chemistry, particularly for nucleic acids, polyanions whose biological functions are intimately related to their high charge density. In the cell, complexation by basic proteins condenses DNA into chromatin, and membraneless organelles formed by liquid–liquid phase separation of RNA and proteins perform vital functions and have been linked to disease. Electrostatic interactions are also the primary method used for assembly of nanoparticles to deliver therapeutic nucleic acids into cells. This work describes complexation experiments with oligonucleotides and cationic peptides spanning a wide range of polymer lengths, concentrations, and structures, including RNA and methylphosphonate backbones. We find that the phase of the complexes is controlled by the hybridization state of the nucleic acid, with double-stranded nucleic acids forming solid precipitates while single-stranded oligonucleotides form liquid coacervates, apparently due to their lower charge density. Adding salt “melts” precipitates into coacervates, and oligonucleotides in coacervates remain competent for sequence-specific hybridization and phase change, suggesting the possibility of environmentally responsive complexes and nanoparticles for therapeutic or sensing applications

Oligonucleotide–Peptide Complexes: Phase Control by Hybridization

When oppositely charged polymers are mixed, counterion release drives phase separation; understanding this process is a key unsolved problem in polymer science and biophysical chemistry, particularly for nucleic acids, polyanions whose biological functions are intimately related to their high charge density. In the cell, complexation by basic proteins condenses DNA into chromatin, and membraneless organelles formed by liquid–liquid phase separation of RNA and proteins perform vital functions and have been linked to disease. Electrostatic interactions are also the primary method used for assembly of nanoparticles to deliver therapeutic nucleic acids into cells. This work describes complexation experiments with oligonucleotides and cationic peptides spanning a wide range of polymer lengths, concentrations, and structures, including RNA and methylphosphonate backbones. We find that the phase of the complexes is controlled by the hybridization state of the nucleic acid, with double-stranded nucleic acids forming solid precipitates while single-stranded oligonucleotides form liquid coacervates, apparently due to their lower charge density. Adding salt “melts” precipitates into coacervates, and oligonucleotides in coacervates remain competent for sequence-specific hybridization and phase change, suggesting the possibility of environmentally responsive complexes and nanoparticles for therapeutic or sensing applications

Ternary, Tunable Polyelectrolyte Complex Fluids Driven by Complex Coacervation

Complex coacervation was achieved by combining poly­(allylamine) (PAH) or branched poly­(ethylenimine) (PEI) with poly­(acrylic acid) (PAA) and poly­(<i><i>N,N</i></i>-dimethylaminoethyl methacrylate) (PDMAEMA). We systematically investigated the effects of stoichiometry, salt concentration, and pH. Ternary coacervates formed over a broader range of stoichiometries compared to the base PAA/PDMAEMA system. An enhanced resistance to salt, that is, resistance to dissolution of the complex with added salt, was observed for ternary coacervates. PEI-containing systems showed a considerable difference in salt resistance at pH 6–8 due to the dramatic change in charge density. This change was interpreted in the context of a theoretical treatment that relies on the Voorn–Overbeek model for free energy. Coacervate stability and viscoelastic behavior were affected by stoichiometry, salt, and pH. Ternary coacervates maintain the characteristics and tunability of typical binary coacervates, but the choice of the third component is important, as it significantly affects the response and material properties

Interfacial Tension of Polyelectrolyte Complex Coacervate Phases

We consider polyelectrolyte solutions which, under suitable conditions, phase separate into a liquid-like coacervate phase and a coexisting supernatant phase that exhibit an extremely low interfacial tension. Such interfacial tension provides the basis for most coacervate-based applications, but little is known about it, including its dependence on molecular weight, charge density, and salt concentration. By combining a Debye–Hückel treatment for electrostatic interactions with the Cahn–Hilliard theory, we derive explicit expressions for this interfacial tension. In the absence of added salts, we find that the interfacial tension scales as <i>N</i>^–3/2(η/η_c–1)^3/2 near the critical point of the demixing transition, and that it scales as η^1/2 far away from it, where <i>N</i> is the chain length and η measures the electrostatic interaction strength as a function of temperature, dielectric constant, and charge density of the polyelectrolytes. For the case with added salts, we find that the interfacial tension scales with the salt concentration ψ as <i>N</i>^–1/4(1−ψ/ψ_c)^3/2 near the critical salt concentration ψ_c. Our predictions are shown to be in quantitative agreement with experiments and provide a means to design new materials based on polyelectrolyte complexation