title: Detecting selection for negative design in proteins through an improved model of the misfolded state.
abstract: Proteins that need to be structured in their native state must be stable both against the unfolded ensemble and against incorrectly folded (misfolded) conformations with low free energy. Positive design targets the first type of stability by strengthening native interactions. The second type of stability is achieved by destabilizing interactions that occur frequently in the misfolded ensemble, a strategy called negative design. Here, we investigate negative design adopting a statistical mechanical model of the misfolded ensemble, which improves the usual Gaussian approximation by taking into account the third moment of the energy distribution and contact correlations. Applying this model, we detect and quantify selection for negative design in most natural proteins, and we analytically design protein sequences that are stable both against unfolding and against misfolding.
authors.affiliation: Institut für Festkörperphysik, Technische Universität Darmstadt, Darmstadt, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Minning
authors.forename: Markus
authors.initials: M
authors.lastname: Porto
authors.forename: Ugo
authors.initials: U
authors.lastname: Bastolla
mesh_terms: D000595:Amino Acid Sequence; D019277:Entropy; D057927:Hydrophobic and Hydrophilic Interactions; D008962:Models, Theoretical; D011487:Protein Conformation; D017510:Protein Folding; D055550:Protein Stability; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D011506:Proteins