Investigation of Polymer Conjugated Helix Bundle Peptides to Design Micellar Nanocarriers with Tunable Size and Stability using Molecular Dynamics

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Hybrid polymer-peptide conjugates are receiving increasing attention as a promising class of biomaterials. Polymer conjugated coiled-coil peptides are a new addition to these designer macromolecules. Even though a variety of experiments and computational simulations have shown stabilization of helices upon polymer conjugation, there are still many questions regarding the conformations of the attached polymer chains and their effects on the thermomechanical and aggregation behavior of peptides. Here, we first investigate the self-assembly of coiled-coils with single polymer chains covalently conjugated to either the end or side, and compare with no polymer conjugation. Our results ascertain polymer stabilization effects on both structural and thermodynamical properties of the peptides. Next, based on scaling theory for tethered polymers, we study multiple polymer chain conjugation to investigate the effect of conjugation density on the stability of coiled-coils and to explore the mushroom conformation of polymer chains on the helix surface. Our findings reveal the molecular mechanisms underpinning recent experimental observations on the stability of protein–PEG conjugates and lay the groundwork for development of stable protein bundles that can serve as drug delivery vehicles, nanocarriers and other biomechanical building blocks. Building on these findings, we focus on a recent design that has utilized end-conjugation of alkyl chains to 3-helix coiled-coils to achieve amphiphilicity, combined with the side-chain conjugation of polyethylene glycol (PEG) to tune micelle size through entropic confinement forces. Next, we investigate this phenomenon in depth, using micelle theory and coarse-grained dissipative particle dynamics (DPD) simulations in an explicit solvent. We analyze the conformations of the PEG chains conjugated to three different positions on 3-helix bundle peptides to observe the degree of confinement upon assembly, as well as the ordering of the subunits making up the micelle. We discover that the micelle size and stability is dictated by competition between the entropy of the PEG chain conformations in the assembled state and intermolecular cross-interactions among PEG chains that promote cohesion between neighboring conjugates. Our analyses build on the role of PEG molecular weight and conjugation site in micelle shape and lead to computational phase diagrams that can be used to design 3-helix micelles. This work opens pathways for the design of multifunctional micelles with tunable size, shape and stability. Homomeric micelles with tunable size, shape and stability have been extensively studied for biomedical applications such as drug carriers. However, designing the local valency and self-assembled morphology of nanophase-separated multicomponent micelles with varied ligand binding sites remains challenging. Finally, we present micelles self-assembled from amphiphilic peptide-PEG-lipid hybrid conjugates, where the peptides can be either 3-helix or 4-helix coiled-coils. We demonstrate that the micelle size and sphericity can be controlled based on the coiled-coil oligomeric state. Using theory and coarse-grained dissipative particle dynamics (DPD) simulations in an explicit solvent simulation, we studied the distribution of 3-helix and 4-helix conjugates within the mixed micelles and observed self-organization into nanodomains within the mixed micelle. We discover that the phase separation behavior is dictated by the geometry mismatch in alkyl chain length from different coiled-coil oligomeric states. Our analyses on the self-assembly tendency and drug delivery potency of mixed micelles with controlled multivalency provide further important insights into the assembly and formation of nanophase-separated micelles.

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  • 04/01/2019
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