STATISTICAL-MECHANICS OF THE COMBINATORIAL SYNTHESIS AND ANALYSIS OF FOLDING MACROMOLECULES

Combinatorial chemistry techniques provide a promising route to the de sign of macromolecules that acquire predetermined folded conformations . A library of sequences based on a pool of different monomer types da n be synthesized, where the sequences are partially designed so as to be consistent with a particular target conformation. The library is sc reened for folding molecules. The number of sequences grows rapidly wi th the length of the polymer, however, and both the experimental and c omputational tabulation of sequences become infeasible. For polymers a nd libraries of arbitrary size; we present a self-consistent, mean-fie ld theory that can be used to estimate the number of sequences as a fu nction of the energy in a target structure. The theory also yields the probabilities that each position in the sequence is occupied by a par ticular monomer type. The theory is tested using a simple lattice mode l of proteins, and excellent agreement between the theory and the resu lts of exact enumerations are observed. The theory may be used to quan tify particular design strategies and the facility of finding low-ener gy sequences for particular structures. The theory is discussed with a n eye toward protein design and the mutability of particular residues in known proteins.