David Brownholland

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Assistant Professor of Chemistry
B.S. Chemistry and B.A. Molecular, Cellular, and Developmental Biology, University of California; Santa Cruz, 2002
Ph.D., Purdue University, 2008

For more details, see my curriculum vitae.

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Research and Activities

Centenary Students: Please contact me directly if you are interested in doing research with me in the fall or spring semesters of the 2010-2011 academic school year. I am happy to consider any student who has, is, or will be taking organic chemistry, regardless of major. Students who work with me in the academic year will have priority for available summer positions.

My research involves the design, synthesis and characterization of unique materials designed to form synthetic lipid membranes. Traditional phospholipid membranes (composed of monopolar phospholipids) form bilayer membranes with phospholipids on opposing leaflets of the bilayer. These membranes are used in a wide variety of applications, including: drug delivery, chemical and biological sensors, and methods of assaying membrane protein activity and function. Unfortunately, these membranes are susceptible to degradation from mechanical, temperature, chemical, and osmotic stress. Bipolar phospholipids, or bolalipids, are commonly found in Archaea and present an interesting alternative. Archaea are organisms which live in extreme environments (e.g., high and low temperatures, high salt concentration and low pH) and have evolved membranes that include significant amounts of bolalipids to increase the membranesí stability.1,2

Figure 1: Difference between monopolar phospholipids and bolalipids
Figure 1: Difference between monopolar phospholipids and bolalipids

Bolalipids address the need for enhanced chemical stability through the presence of rugged ether-linkages, as opposed to the fragile ester-linked monopolar phospholipids. Another distinctive feature of bolalipids is the presence of transmembrane chains (fatty chains that extend through the entire membrane), which are believed to be partially responsible for their enhanced stability (Figure 1).1,2 Bolalipids have demonstrated potential in applications such as lipid membrane-based biosensors,3-5 drug-, gene-6 and vaccine delivery vehicles,7 and as molecular fossils.8 Archaeal lipids are a diverse group of compounds which contain a large number of unusual functional groups and, despite some recent advances; it is poorly understood how the functional groups affect the bolalipid membrane properties.

The largest obstacle to studying and utilizing bolalipids has been availability. Incubating Archaea is difficult; thus, bolalipid extracts from these natural sources are extremely expensive. Further, these bulk extracts are impure and consequently are poorly characterized. These barriers have led to a growing need for the total synthesis of natural bolalipids and bolalipid analogues. Several groups have made significant strides in the synthesis of these materials,4,6,9-14 but much work is still needed to realize their full potential. This necessary work includes the synthesis of more complex bolalipids and increasing the efficiency of the synthesis. The synthesis of a greater diversity of bolalipids will allow for a thorough understanding of the structure/function relationships of these lipids and will, in turn, allow for more efficient bolalipids to be designed, synthesized and utilized.

I plan to expand the current family of synthesized bolalipids (Figure 2) and, through collaborations, use a series of well-established biophysical techniques to gain a better understanding of the effects of differing functional groups of bolalipids on the physical properties of membranes containing them. Several techniques have been utilized to study membranes composed of bolalipids, including 31P NMR anisotropy,15 differential scanning calorimetry (DSC),9,15 atomic force microscopy (AFM),16 deuterium NMR spectroscopy,10,17,18 fluorescence recovery after photobleaching (FRAP),15 fluorescence imaging,19 small-angle X-ray spectroscopy (SAXS)18 and pulsed-field gradient NMR (PFG-NMR).15 These techniques offer insight into the physical nature of bolalipid membranes, their fluidity, melting transition, segmental order parameters of the headgroups and alkyl groups, hydration level, as well as homogeneity and mixing behavior with other lipids.

Figure 2: Target Molecules
Figure 2: Target Molecules

1. De Rosa, M.; Gambacorta, A., Progress in Lipid Research 1988, 27, (3), 153-175.

2. Fuhrhop, A. H.; Wang, T. Y., Chemical Reviews 2004, 104, (6), 2901-2937.

3. Cornell, B. A.; Braach-Maksvytis, V. L. B.; King, L. G.; Osman, P. D. J.; Raguse, B.; Wieczorek, L.; Pace, R. J., Nature 1997, 387, (6633), 580-583.

4. Kim, J. M.; Patwardhan, A.; Bott, A.; Thompson, D. H., Biochimica Et Biophysica Acta, Biomembranes 2003, 1617, (1-2), 10-21.

5. Veld, G. I.; Elferink, M. G. L.; Driessen, A. J. M.; Konings, W. N., Biochemistry 1992, 31, (49), 12493-12499.

6. Benvegnu, T.; Cammas-Marion, L. L. S., European Journal of Organic Chemistry 2008, 2008, (28), 4725-4744.

7. Patel, G. B.; Sprott, G. D., Critical Reviews in Biotechnology 1999, 19, (4), 317-357.

8. Huguet, C.; Hopmans, E. C.; Febo-Ayala, W.; Thompson, D. H.; Damste, J. S. S.; Schouten, S., Organic Geochemistry 2006, 37, (9), 1036-1041.

9. Febo-Ayala, W.; Morera-Felix, S. L.; Hrycyna, C. A.; Thompson, D. H., Biochemistry 2006, 45, (49), 14683-14694.

10. Holland, D. P.; Struts, A. V.; Brown, M. F.; Thompson, D. H., Journal of the American Chemical Society 2008, 130, (14), 4584-4585.

11. Patwardhan, A. P.; Thompson, D. H., Langmuir 2000, 16, (26), 10340-10350.

12. Thompson, D. H.; Wong, K. F.; Humphry-Baker, R.; Wheeler, J. J.; Kim, J. M.; Rananavare, S. B., Journal of the American Chemical Society 1992, 114, (23), 9035-9042.

13. Benvegnu, T.; Brard, M.; Plusquellec, D., Current Opinion in Colloid & Interface Science 2004, 8, (6), 469-479.

14. Sun, X. L.; Biswas, N.; Kai, T.; Dai, Z. F.; Dluhy, R. A.; Chaikof, E. L., Langmuir 2006, 22, (3), 1201-1208.

15. Febo-Ayala, W.; Holland, D. P.; Bradley, S. A.; Thompson, D. H., Langmuir 2007, 23, (11), 6276-6280.

16. Mulligan, K.; Brownholland, D.; Carnini, A.; Thompson, D.; Johnston, L., Langmuir 2010, in press.

17. Cuccia, L. A.; Morin, F.; Beck, A.; Hebert, N.; Just, G.; Lennox, R. B., Chemistry—a European Journal 2000, 6, (23), 4379-4384.

18. Brownholland, D. P.; Longo, G.; Struts, A. V.; Justice, M. J.; Szleifer, I.; Petrache, H. I.; Brown, M. F.; Thompson, D. H., Biophysical Journal 2009, 97, 2700-2709.

19. Unpublished work, Mulligan, K.; Brownholland, D.; Carnini, A.; Thompson, D.; Johnston, L.

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