PRINCIPLES OF PROTEIN-FOLDING - A PERSPECTIVE FROM SIMPLE EXACT MODELS

General principles of protein structure, stability, and folding kineti cs have recently been explored in computer simulations of simple exact lattice models. These models represent protein chains at a rudimentar y level, but they involve few parameters, approximations, or implicit biases, and they allow complete explorations of conformational and seq uence spaces. Such simulations have resulted in testable predictions t hat are sometimes unanticipated: The folding code is mainly binary and delocalized throughout the amino acid sequence. The secondary and ter tiary structures of a protein are specified mainly by the sequence of polar and nonpolar monomers. More specific interactions may refine the structure, rather than dominate the folding code. Simple exact models can account for the properties that characterize protein folding: two -state cooperativity, secondary and tertiary structures, and multistag e folding kinetics - fast hydrophobic collapse followed by slower anne aling. These studies suggest the possibility of creating ''foldable'' chain molecules other than proteins. The encoding of a unique compact chain conformation may not require amino acids; it may require only th e ability to synthesize specific monomer sequences in which at least o ne monomer type is solvent-averse.