A study of energy minimization techniques applied to protein design
  We present a detailed study of the performance and reliability of design procedures based on energy minimization. The analysis is carried out for model proteins where exact results can be obtained through exhaustive enumeration. The efficiency of design techniques is assessed as a function of protein lengths and number of classes into which amino acids are coarse grained. It turns out that, while energy minimization strategies can identify correct solutions in most circumstances, it may be impossible for numerical implementations of design algorithms to meet the efficiency required to yield correct solutions in realistic contexts. We also investigated how the design efficiency varies when putative solutions are required to obey some external constraints and found that a restriction of the sequence space impairs the design performance rather than boosting it. Finally some alternate design strategies based on a correct treatment of the free energy are discussed. These are shown to be significantly more efficient than energy-based methods while requiring nearly the same CPU time. 
Cristian Micheletti and Amos Maritan