- Perla focuses on macromolecules rather than simpler organic compounds. So far, there is only one algorithm with a similar scope. - Perla evaluates the difference in potential energy between two states, the target conformation and a reference state. In opposition to the simple organic compounds, weak non-covalent forces maintain the active three-dimensional structure of macromolecules. Hence, this active conformation is always in equilibrium with an ensemble of unspecific and inactive configurations. Treating this ensemble with the same accuracy as the Target State enables to optimize the equilibrium to the advantage of the practical application. - Perla uses a custom-made library of side chain conformation (rotamers). The configurations were determined with a rigorous fitting of the occurrence of conformation in the protein database to Gaussain distributions. Since setero chemical rules were not used to define the rotamers, less abundant but relevant side chain structures were obtained. In addition, the fitted normal distribution defined the margins within which the rotamers can oscillate. Adaptation of the rotamers from the library to the target structure is then obtained by means of energy optimization (conjugate-gradient minimization and sampling of sud-rotamers). - The combinatorial problem of side chain building is solved using the Mean Field Theory that was previously utilized to predict the conformation of side chains for known protein structures. The integration into a protein engineering algorithm is novel. The method has the advantage to provide a measure of the entrophy of the molecule. All possible conformations are considered, rather than the sole energy minimum. Therefore, Perla describes in a better way what macromolecules are and how they behave. - Perla uses a scoring system function consisting in a sum of terms. Usually, optimal sequences are selected according only to the global sum. Perla requires that all the individual terms satisfy determined constraints, as occurring in natural proteins. - Perla can be used to engineer and design protein multimers (homo- and hetro-polymers).