CHARMM force field and molecular dynamics simulations of protonated polyethylenimine

5 years ago

CHARMM force field and molecular dynamics simulations of protonated polyethylenimine

Alexandra Farcaş, Titus Adrian Beu

As a gene delivery vector, polyethylenimine (PEI) shows one of the highest transfection efficiencies, while effectively protecting DNA from enzyme degradation. The distinctive charge pattern of protonated PEI is widely considered responsible for fundamental process such as DNA condensation into PEI/DNA polyplexes (which are able to enter cells via endocytosis), proton sponge effect (which triggers the release of polyplexes from endosome), and release of DNA from polyplexes (to be further processed inside the nucleus). Our investigations are largely motivated by the crucial need for a realistic molecular mechanics force field (FF) for PEI, and, accordingly, we focus on two major issues: (1) development of a new atomistic (CHARMM) FF for PEI in different protonation states, rigorously derived from high-quality ab initio calculations performed on model polymers, and (2) molecular dynamics investigations of solvated PEI, providing a detailed picture of the dynamic structuring thereof in dependence on their size and protonation state. The modeled PEI chains are essentially described in terms of gyration radius, end-to-end distance, persistence length, radial distribution functions, coordination numbers, and diffusion coefficients. They turn out to be more rigid than in other computational studies and we find diffusion coefficients in fair agreement with experimental data. The developed atomistic FF proves adequate for the realistic modeling of the size and protonation behavior of linear PEI, either as individual chains or composing polyplexes. © 2017 Wiley Periodicals, Inc. Polyethylenimine (PEI) is used as carrier in modern delivery protocols of DNA to cell nuclei, which synthesize gene products relevant to curing various diseases. The ability of PEI chains to wrap and condense DNA into polyplexes able to enter cells, crucially depends on their structural features and charge distribution. We optimize their design by constructing a new, realistic molecular force field for PEI and perform numerical simulations to elucidate the interplay between the various properties.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/jcc.24890