Folding the main chain of small proteins with the genetic algorithm.

Grid-free protein folding simulations were effected using the genetic algorithm, a backbone representation and standard dihedral angular conformations. The topological folding of idealized four-helix bundles was investigated in detail to differentiate among the important protein folding forces used as fitness criteria. Hydrophobic interactions were the most significant while local forces and hydrogen bonds were far less effective in promoting folding. Stable secondary structural regions were also important as nucleating centers. Using the fitness parameters optimized in idealized simulations together with standard secondary structure predictions derived from the amino acid sequence alone, the proper main-chain folding of the four-helix bundle proteins cytochrome b562, cytochrome c' and hemerythrin was achieved. In addition the backbone topology as predicted by the genetic algorithm for crambin, a mixed helix/strand protein with known structure, is presented and discussed.