A comparative study of existing and new design techniques for protein models

We present a detailed study of the performance and reliability of design pr ocedures based on energy minimization. The analysis is carried out for mode l proteins where exact results can be obtained through exhaustive enumerati on. The efficiency of design techniques is assessed as a function of protei n length and the number of classes into which amino acids are coarse graine d. It turns out that, while energy minimization strategies can identify cor rect solutions in most circumstances, it may be impossible for numerical im plementations of design algorithms to meet the efficiency required to yield correct solutions in realistic contexts. Alternative design strategies bas ed on an approximate treatment of the free energy are shown to be much more efficient than energy-based methods while requiring nearly the same CPU ti me. Finally, we present a novel iterative design strategy that incorporates negative design with the use of selected decoy structures that compete sig nificantly with the target native state in housing the designed sequences. This procedure allows one to identify systematically all sequences that fol d on a given target structure. (C) 1999 American Institute of Physics. [S00 21-9606(99)51219-1].