Evidence against the paradigm of energy minimization in protein design

Stating protein design as an energy minimization in the space of amino acid sequences and rotamer combinations is usual. In the current paper an evolutionary algorithm built on this paradigm is presented, where each candidate sequence is threaded by SCWRL onto a fixed backbone structure and the energy of the resulting protein is estimated by FOLD-X. The high accuracy of such an estimate provides grounds for the hypothesis that the lowestenergy sequences may not fold into the input backbone structure, since the algorithm easily finds sequences that have a lower FOLD-X energy than the native sequence and are very different from it.