The Core Repacking Problem

The burial of hydrophobic groups is the dominant force determining the folding of an unstructured polypeptide to a functional protein (Dill 1990). Protein cores are composed of nonsequential residues distributed throughout the polypeptide chain that are isolated from exterior solvent and interact primarily via van der Waals (vdW) and hydrophobic forces in the interior of the protein. Cores are characteristically well-packed and lack cavities, and mutational data have shown that mutations in the core often affect thermostability while maintaining the tertiary structure of the protein (Lim et al. 1992; Eriksson et al. 1993; Milla et al. 1994; Munson et al. 1996; Vlassi et al. 1999). The importance of the core to stability and its observed ability to withstand mutation made it an ideal subject for the earliest work in protein design (Hurley et al. 1992; Desjarlais and Handel 1995; Lazar et al. 1997). Restricting the design to core positions and hydrophobic residues reduces the combinatorial problem considerably, as well as simplifying or eliminating the need to model complex solvent interactions present at the protein surface. The dominance of hydrophobic interactions in the core made a simple vdW term sufficient for some problems, which could be modeled using a standard Lennard-Jones 6-12 potential.

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