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1200 E. California Blvd.
Pasadena, CA
91125-9600
Mail Code: 114-96
Location: 151 Broad
Phone: (626) 395-8846
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Research
The production of novel proteins with prescribed properties requires
five underpinning and complementary abilities: (i) the ability to
predict the most stable fold of a particular sequence, (ii) the
ability to design a novel fold, (iii) the ability to predict whether
the desired fold is kinetically accessible, (iv) the ability to
design the precise features for specific binding and/or efficient
catalytic function in the fold, (v) the ability to dictate assembly
with precise orientation (Fersht, 1999). Currently, each of the
five prerequisites is beyond any practical application for average
length proteins. However, the existence of a funneled landscape
for both folding and binding/assembly processes suggests that proteins
are evolutionarily designed to follow the principle of minimal frustration
(Bryngelson and Wolynes, 1987), which results in a faster search
through the many alternatives in the cell and affords considerable
robustness of binding/assembly capability against possible mutations.
The funneled landscape leading toward the native bound configuration
guarantees that binding and assembly will also be stable against
environmental and evolutionary fluctuations. Moreover, the principle
of minimal frustration and the funnel concept has been extended
to explain different binding mechanisms (Ma et
al., 1999), enzyme pathways and allostery (Kumar et
al., 2000; Verkhivker et al., 2002) aspects of binding
selectivity and specificity (Wang
and Verkhivker, 2003). Thus, the goal of my investigation is to
effectively consolidate the folding, assembly, binding, and allosteric
mechanisms. The results from these studies will ultimately result
in more effective interpretations of experimental results and the
development of new approaches for mechanistic analysis and design
in other protein families.
References
Bryngelson, J. D., and Wolynes, P. G. (1987). Spin glasses and the
statistical mechanics of protein folding. Proc Natl Acad Sci U S
A 84, 7524-7528.
Fersht, A. (1999). Structure and mechanism in protein science (New
York: W.H. Freeman and Company).
Kumar, S., Ma, B., Tsai, C. J., Sinha, N., and Nussinov, R. (2000).
Folding and binding cascades: dynamic landscapes and population shifts.
Protein Sci 9, 10-19.
Ma, B., Kumar, S., Tsai, C. J., and Nussinov, R. (1999). Folding funnels
and binding mechanisms. Protein Eng 12, 713-720.
Verkhivker, G. M., Bouzida, D., Gehlhaar, D. K., Rejto, P. A., Freer,
S. T., and Rose, P. W. (2002). Complexity and simplicity of ligand-macromolecule
interactions: the energy landscape perspective. Curr Opin Struct Biol 12,
197-203.
Wang, J., and Verkhivker, G. M. (2003). Energy landscape theory, funnels,
specificity, and optimal criterion of biomolecular binding. Phys Rev
Lett 90, 188101.
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