Can we characerize the sequence space compatible with a protein structure?
Michael Levitt (Stanford University)
What is the Inverse protein folding problem ?
The inverse folding problem was originally defined by Drexler  and Pabo  as the problem of defining the sequences compatible with a given protein fold. It is fundamental to protein design and engineering, and, as such, as attracted considerable interest [3-8]. Since the function of a protein is directly related to its three dimensional structure, manipulation of the structure via the sequence changes can provide functional diversity. Protein molecules can be engineered to optimize their activities, as well as to alter their pharmacokinetic properties.
The aim of protein sequence design is to generate sequences compatible with the target structure, but incompatible with competing folds. As such, there is one theoretical issue, and one computational problem to be solved. Here we provide links to general reviews that cover both subjects:
Our Strategy for Protein Sequence Design
This link describes the method we have developed for solving this problem.
References1. Drexler, KE. Molecular engineering: an approach to the development of general capabilities for molecular manipulation. Proc. Natl. Acad. Sci. (USA), 78, 5275-5278 (1981).
2. Pabo, C. Designing proteins and peptides. Nature, 301, 200 (1983).
3. Mutter, M and Tuchscherer, G. Nonnative Architectures In Protein Design and Mimicry. Cellular and Molecular Life Sciences, 53, 851-863 (1997).
4. Smith, CK and Regan, L. Construction and Design Of Beta-Sheets. Accounts Of Chemical Research, 30, 153-161 (1997).
5. Cao, AN, Lai, LH and Tang, YQ. The Current State and Prospect Of De-Novo Protein Design. Progress In Biochemistry and Biophysics, 25, 197-201 (1998).
6. Giver, L and Arnold, FH. Combinatorial Protein Design By In-Vitro Recombination. Current Opinion In Chemical Biology, 2, 335-338 (1998).
7. Regan, L and Wells, J. Engineering and Design. Recent adventures in molecular design. Curr. Opin. Struct. Biol., 8, 441-442 (1998).
8. Shakhnovich, EI. Protein Design : a Perspective From Simple Tractable Models. Folding & Design, 3, R45-R58 (1998).