Folding and misfolding of designed proteinlike chains with mutations

We study the impact of mutations (changes in amino acid sequence) on the thermodynamics of simple proteinlike heteropolymers consisting of N monomers, representing the amino acid sequence. The sequence is designed to fold into its native conformation on a cubic lattice. It is found that quite a large fraction, between one-half and one-third of the substitutions, which we call "cold errors," make important contributions to the dynamics of the folding process, increasing folding times typically by a factor of 2, the altered chain still folding into the native structure. Few mutations ("hot errors"), have quite dramatic effects, leading to protein misfolding. Our analysis reveals that mutations affect primarily the energetics of the native conformation and to a much lesser extent the ensemble of unfolded conformations, corroborating the utility of the "energy gap" concept for the analysis of folding properties of proteinlike heteropolymers. © 1998 American Institute of Physics.