Abstract
Polyethylene glycol (PEG) has been conjugated to many drugs or drug carriers to increase their solubility and circulating lifetime, and reduce toxicity. This has motivated many experimental studies to understand the effect of PEGylation on delivery efficiency. To complement the experimental findings and uncover the mechanism that cannot be captured by experiments, all-atom and coarse-grained molecular dynamics (MD) simulations have been performed. This has become possible, due to recent advances in simulation methodologies and computational power. Simulations of PEGylated peptides show that PEG chains wrap antimicrobial peptides and weaken their binding interactions with lipid bilayers. PEGylation also influences the helical stability and tertiary structure of coiled-coil peptides. PEGylated dendrimers and single-walled carbon nanotubes (SWNTs) were simulated, showing that the PEG size and grafting density significantly modulate the conformation and structure of the PEGylated complex, the interparticle aggregation, and the interaction with lipid bilayers. In particular, simulations predicted the structural transition between the dense core and dense shell of PEGylated dendrimers, the phase behavior of self-assembled complexes of lipids, PEGylated lipids, and SWNTs, which all favorably compared with experiments. Overall, these new findings indicate that simulations can now predict the experimentally observed structure and dynamics, as well as provide atomic-scale insights into the interactions of PEGylated complexes with other molecules.
Highlights
Polyethylene oxide (PEO) and polyethylene glycol (PEG) are polymers with the formulas, respectively, H3C–O–(CH2–CH2–O)n–CH3 and HO–(CH2–CH2–O)n–H, which have been widely used to replace various membranes, solvents, and nanocomposites for chemical, biomedical, and manufacturing applications
The all-atom models for PEO and PEG have been parameterized to reproduce free energies and conformer populations calculated from quantum chemistry calculations, which were again used to parameterize CG models
The CG models have been applied to large-scale systems such as the self-assembly of PEG and other molecules, and the interaction with lipid bilayers
Summary
Polyethylene oxide (PEO) and polyethylene glycol (PEG) are polymers with the formulas, respectively, H3C–O–(CH2–CH2–O)n–CH3 and HO–(CH2–CH2–O)n–H, which have been widely used to replace various membranes, solvents, and nanocomposites for chemical, biomedical, and manufacturing applications. Stepniewski et al parameterized PEGs with the OPLS all-atom force field and simulated the bilayer composed of PEGylated lipids, showing the electrostatic interaction between ions and PEG oxygens, and the penetration of PEGs into the hydrophobic region of the lipid bilayer in the liquid phase [34] These all-atom models can accurately predict the conformation and structure of PEGs and their interactions with other molecules, their system size and time scale are limited. This CG model was reparameterized by the Monticelli group, which has an increased time step, while maintaining the accurate prediction of PEG conformation [46]. Unlike other CG models, the CG model of mapping two monomers onto one bead was developed [47]
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