  We propose and discuss a novel strategy for protein design. The method is
based on recent theoretical advancements which showed the importance to treat
carefully the conformational free energy of designed sequences. In this work we
show how computational cost can be kept to a minimum by encompassing negative
design features, i.e. isolating a small number of structures that compete
significantly with the target one for being occupied at low temperature. The
method is succesfully tested on minimalist protein models and using a variety
of amino acid interaction potentials.
