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Structural characterization of an amine-terminated hybrid dendrimer:
molecular dynamics studies

Inhan Leea, Istvan Majorosa, Brian D. Atheyb, Donald A. Tomaliaa, James R. Baker, Jr.*, a

aDepartment of Internal Medicine and Center for Biologic Nanotechnology, University of Michigan,
Ann Arbor, MI 48109 USA

bDepartment of Anatomy and Cell Biology, University of Michigan

This is an abstract for a presentation given at the
Eighth Foresight Conference on Molecular Nanotechnology.
There will be a link from here to the full article when it is available on the web.


Polyamidoamine (PAMAM) dendrimers have been successfully used as gene transfection vectors due to the primary amines on their surface and interior tertiary amines. Amine-terminated poly(propyleneimine) (DAB-dendr-(NH2)x) dendrimers also have the same primary and tertiary amine numbers as EDA-core PAMAM dendrimers; however, their gene delivery ability is much poorer than that of PAMAM, and they are toxic in biological applications. Since the synthesis of DAB-dendr-(NH2)x is more straightforward than that of PAMAM, we developed and successfully synthesized hybrid dendrimers of DAB-dendr-(NH2)x and PAMAM (POMAM) so that PAMAM shells attached to the core of DAB-dendr-(NH2)x dendrimers.

There have been numerous molecular dynamics studies on dendrimers in good correlation with experimental results. However, no simulation study on dendrimers with protonated-amines has been done, to our knowledge, although most primary amines are protonated in physiological conditions. The locations of end-terminal amines, which are very important in both biological interactions and chemical synthesis, have not been well characterized either. This molecular dynamics study characterized the biological functionality of dendrimers depending on the location of primary amines in amine-terminated dendrimers as a function of protonation.

EDA-core PAMAM dendrimer generation 3 (PAMAM G3), DAB-dendr-(NH2)32, and hybrid dendrimer of DAB-dendr-(NH2)16 core and one PAMAM shell (POMAM 21) were modeled using InsightII (Molecular Simulations, Inc.) software on a Silicon Graphics, Inc. Onyx workstation, minimizing the structure of each step. These three kinds of dendrimers were then modeled with all amines protonated. Molecular dynamics simulations of different dendrimers at different amine conditions were performed using the Discover module of InsightII with cvff forcefield for 200 psec with 1 fsec time intervals at 295 oK in vacuum after global minimization. The probabilities of the primary amine locations were prepared by in-house program and plotted with Gaussian function.

PAMAM G3, DAB-dendr-(NH2)32, and POMAM 21 all have 32 primary amines and 28 tertiary amines, while the branch length of poly(propyleneimine) is much shorter than that of PAMAM. Dendrimers with fully protonated amines presented a narrower distribution of primary amines than those without, showing fully stretched structures. In the case of protonated amines, the overall values of primary amine locations of POMAM 21 is closer to that of DAB-dendr-(NH2)32, with a distinctive two-peak distribution of primary amines, while PAMAM G3 presented a broader peak of a composition of four Gaussian functions. Without protonation, the mean values of primary amine location in a hybrid dendrimer shifted toward PAMAM G3. These results suggest that within the confines of a fully-protonated amine structure, the gene transfection ability of hybrid dendrimers may approach that of PAMAM.

*Corresponding Address:
James R. Baker, Jr.
Department of Internal Medicine and Center for Biologic Nanotechnology, University of Michigan
1150 W. Medical Center Dr., 9220 MSRB III
Ann Arbor, MI 48109 USA


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