title: Coarse-grained modeling study of nonpeptide RGD ligand density and PEG molecular weight on the conformation of poly(γ-glutamyl-glutamate) paclitaxel conjugates.
abstract: Molecular shape, flexibility, and surface hydrophilicity are thought to influence the ability of nanoparticles to cross biological barriers during drug delivery. In this study, coarse-grained (CG) molecular dynamics (MD) simulations were used to study these properties of a polymer-drug construct in potential clinical development: poly(γ-glutamyl-glutamate)-paclitaxel-poly(ethylene glycol) nonpeptide RGD (PGG-PTX-PEG-npRGD), a linear glutamyl-glutamate polymer with paclitaxel and poly(ethylene glycol)-nonpeptide RGD side groups. It was hypothesized that the PEG molecular weight (MW) (500 Da; 1,000 Da; and 2,000 Da) and nonpeptide RGD ligand density (4, 8, 12, and 16 per molecule), respectively, may have advantageous effects on the shape, flexibility, and surface hydrophilicity of PGG-PTX-PEG-npRGD. Circular dichroism spectroscopy was used to suggest initial structures for the all-atom (AA) models of PGG-PTX-PEG-npRGD, which were further converted to CG models using a commercially available mapping algorithm. Due to its semi-flexibility, PGG-PTX-PEG-npRGD is not limited to one specific conformation. Thus, CG MD simulations were run until statistical equilibrium, at which PGG-PTX-PEG-npRGD is represented as an ensemble of statistically similar conformations. The size of a PGG-PTX-PEG-npRGD molecule is not affected by the PEG MW or the nonpeptide RGD density, but higher PEG MW results in increased surface density of a PGG-PTX-PEG-npRGD molecule. Most PGG-PTX-PEG-npRGD shapes are globular, although filamentous shapes were also observed in the PEG500 and PEG1000 molecules. PEG500 and PEG1000 molecules are more flexible than PEG2000 systems. A higher presence of npRGD ligands results in decrease surface hydrophilicity of PGG-PTX-PEG-npRGD. These results indicate that the PGG-PTX-PEG1000-npRGD(4) and PGG-PTX-PEG1000-npRGD(8) molecules are the most efficacious candidates and are further recommended for experimental preclinical studies.
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA. lilipeng@gmail.com
authors.forename: Lili X
authors.initials: LX
authors.lastname: Peng
authors.forename: Sanjib K
authors.initials: SK
authors.lastname: Das
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Howell
authors.forename: David A
authors.initials: DA
authors.lastname: Gough
mesh_terms: D002942:Circular Dichroism; D004151:Dipeptides / Q000737:chemistry*; D005971:Glutamates / Q000737:chemistry*; D008024:Ligands; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D008970:Molecular Weight; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000737:chemistry; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D011506:Proteins / Q000737:chemistry*
chemical_list: D004151:Dipeptides; D005971:Glutamates; D008024:Ligands; D011108:Polymers; D011506:Proteins; C548171:poly(gamma-glutamylglutamine)paclitaxel; C082810:gamma-glutamylglutamate; D011092:Polyethylene Glycols; D017239:Paclitaxel