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interesting only for systems amenable to experimental analysis. However, the examples illustrate how the theory can provide new insights and deeper under- standing of the experiments. As experience with such simulations accumulates and as predictions are made on more and more complex systems amenable to experiment, it will become increasingly feasible to use the theory on unknown systems. As the predictions on such unknown systems are tested with exper- iment and as the reliability of the predictions increases, these techniques will become true design tools for development of new biological systems.
Acknowledgments
This work was funded by a grant from the Department of Energy, Energy Con- version and Utilization Technologies. The DOE-ECUT program funded this work with the hope that development of simulation techniques would eventually have an impact on development of new, industrially useful processes for biotech- nology and biocatalysis. We especially wish to acknowledge the foresight of Drs. Jim Eberhardt, Minoo Dastoor, and Jovan Moacanin in encouraging these efforts. The equipment used was also funded by the ONR/DARPA ( Contract No. N00014-86-K-0735) and by a grant from the Division of Materials Re- search, Materials Research Groups, of the National Science Foundation (Grant No. DMR84-21119). We thank Professor Stephen J. Benkovic of the Pennsylva- nia State University and Dr. Donald A. Tomalia of The Dow Chemical Company for numerous helpful discussions and for materials in advance of publication.
Literature Cited
1. Cytochrome P - 450 : Structure, Mechanism, and Biochemistry; Ortiz de Montecellano, P. R., Ed.; Plenum Press: New York, 1986.
2. Tomalia, D. A.; Baker, H.; Dewald, J.; Hall, M.; Kallas, G.; Martin, S.;
Roeck, J.; Ryder, J.; Smith, P. Macromolecules 1986, 19, 2466-2468.
3. Naylor, A. M.; Goddard III, W. A. Polymer Preprints 1988, 29, 215-216.
4. Tomalia, D. A.; Hall, M.; Hedstrand, D. M. J. Am. Chem. Soc. 1987, 109, 1601-1603.
5. Richards, F. Ann. Rev. Biophys. Bioeng. 1977, .§, 151-176.
6. Kebabian, J. W.; Agui, T.; van Oene, J.C.; Shigematsu, K.; Saavedra, J.
M. Trends in Pharmacological Sciences 1986, 96-99.
7. Greatly, J. E. Adv. Pharma.col. Chemother. 1980, 17, 37-102.
Hamlin, R.; Hol, W. T. J.; Kisliuk, R. L.; Pastore, E. J.; Plante, L. T.;
Xuong, N; Kraut, J. J.Biol.Chem. 1978, 253, 6946-6954.
9. Bolin, J. T.; Filman, D. J.; Matthews, D. A.; Hamlin, R. C.; Kraut, J.
J. Biol. Chem. 1982, 257, 13650-13662.
10. Filman, D. J.; Bolin, J. T.; Matthews, D. A.; Kraut, J. J. Biol. Chem. 1982, 257, 13663-13672.
11. Stone, S. R.; Morrison, J. F. Biochemistry 1984, 23, 2753-2758.
12. Fierke, C. A.; Johnson, K. A.; Benkovic, S. J. Biochemistry 1987, 26, 4085- 4092.
13. Villafranca, J.E.; Howell, E. E.; Voet, D. H.; Strobel, M. S.; Ogden, R. C.;
Abelson, J. N.; Kraut, J. Science 1983, 222, 782-788.
14. Chen, J.-T.; Mayer, R. J.; Fierke, C. A.; Benkovic, S. J. J. Cellular Biochem.
1985, 29, 73-82.
15. Howell, E. E.; Villafranca, J. E.; Warren, M. S.; Oatley, S. J.; Kraut, J.
Science 1986, 231, 1123-1128.
16. Taira, K.; Chen, J.-T.; Fierke, C. A.; Benkovic, S. J. Bull. Chem. Soc. Jpn.
1987, 60, 3025-3030.
17. Mayer, R. J.; Chen, J.-T.; Taira, K.; Fierke, C. A.; Benkovic, S. J.
Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 7718-7720.
18. Weiner, S. J.; Kollman, P.A.; Case, D. A.; Singh, U. C.; Ghio, C.; Alagona, G.; Profeta, Jr., S.; Weiner, P. J. Am. Chem. Soc. 1984, 106, 765-784.
19. Benkovic, S. J .; Fierke, C. A.; Naylor, A. M. Science 1988, 239, 1105-1110.
20. Charlton, P.A.; Young, D. W.; Birdsall, B.; Feeney, J.; Roberts, G. C. K.
J. Chem. Soc., Chem. Commun. 1979, 922-924.
21. Cocco, L.; Temple, Jr., C.; Montgomery, J. A.; London, R. E.; Blakley, R.
L. Biochem. Biophys. Res. Commun. 1981, 100, 413-419.
22. Wu, Y.-D.; Houk, K.N. J. Am. Chem. Soc. 1987, 109, 2226-2227.
Dendritic Macromolecules:
Molecular Simulation of Starburst Dendrimers
The text of this section is part of an article coauthored with William A. Goddard III and Donald A. Tomalia. It is to be submitted to Angewandte Chemie.
erations ( one through three) but adopt more spheroidal structures containing internal hollows connected by channels that run the length of the assembly for generations 5 and above. The studies on these higher generation polymers in- dicate that: (a) ~50% of the surface area is internal, and (b) ~50% of the spheroidal volume is solvent-filled. Such systems provide the opportunity to se- lectively design unique polymers with internal binding sites. The sequestering of dopamine in a catechol-modified starburst dendrimer was modeled to illustrate the potential utility of these dendritic materials as therapeutic delivery systems.
A second class, typified by penta-erythritol polyether dendrimers, is found to have spherical forms at very early generations. For this type, the later generations lack any internal surface area or volume. Calculations of the amount of surface area available to terminal generation hydroxyl groups indicate the dense-packed limit for these polyether dendrimers to be the third generation, consistent with experiment.
A novel class of polymers called "starburst dendrimers" has recently been discovered by Tomalia et aJ.1- 7 These unique polymeric materials (a) start with an initiator unit, termed the "core," which possesses multiple sites for condensa- tion, and (b) use monomer subunits that terminate in functional groups, each of which allows for multiple branching sites. Using various synthetic strategies, it is possible to ensure that these polymers grow in a very systematic manner, produc- ing materials with a well-defined number of monomer subunits and a quantized number of terminal groups, as shown schematically in Figure 1. Thus, the initial condensation of monomers to fully saturate the core unit produces a generation 1 dendrimer. The subsequent condensation of monomers to saturate the terminal functional groups of the generation 1 moiety yields the generation 2 dendrimer.
This process is repeated to create higher generation polymeric dendrimers.
The strategies employed to synthesize this type of polymer involve the selec- tive use of protecting groups5 or multistep condensations1•4 so that each genera- tion can be completed before starting a new one. Thus nearly ideal, synthetically perfect materials can be made for characterization and can be used to proceed to subsequent generations. Unfortunately, even though each molecule has the same topological structure, there are an enormous number of possible conformations (these systems are fractal in nature) so that, despite their uniformity, there is no long-range order for x-ray crystal structure analysis. Thus, to date, there are no detailed experimental structural characterizations to guide the design of these new materials. This work ( using molecular simulations) presents the first such structural characterization of starburst dendrimers. Based on this work, we are able to discuss some properties and possible functional applications.
Figure 1. Schematic two-dimensional representation of a starburst dendrimer growth cascade.
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The molecular simulation studies presented in this work have focused on two types of starburst dendrimers: (a) the polyamidoamines and (b) the penta- erythritol polyethers. The synthetic methods to produce these materials and the experimental characterizations are summarized below.
1.1.1 Polyamidoamine Starburst Dendrimers
The polyamidoamine dendrimers (PAMAM), also referred to as the
/3-
alanine systems, begin with an ammonia core unit (1) and contain the ami- doamine monomer building block (2) shown below.