Trade-off between positive and negative design of protein stability: from lattice models to real proteins

Orly Noivirt-Brik, Amnon Horovitz, R. Unger

Research output: Contribution to journalArticlepeer-review


Two different strategies for stabilizing proteins are (i) positive design in which the native state is stabilized and (ii) negative design in which competing non-native conformations are destabilized. Here, the circumstances under which one strategy might be favored over the other are explored in the case of lattice models of proteins and then generalized and discussed with regard to real proteins. The balance between positive and negative design of proteins is found to be determined by their average “contact-frequency”, a property that corresponds to the fraction of states in the conformational ensemble of the sequence in which a pair of residues is in contact. Lattice model proteins with a high average contact-frequency are found to use negative design more than model proteins with a low average contact-frequency. A mathematical derivation of this result indicates that it is general and likely to hold also for real proteins. Comparison of the results of correlated mutation analysis for real proteins with typical contact-frequencies to those of proteins likely to have high contact-frequencies (such as disordered proteins and proteins that are dependent on chaperonins for their folding) indicates that the latter tend to have stronger interactions between residues that are not in contact in their native conformation. Hence, our work indicates that negative design is employed when insufficient stabilization is achieved via positive design owing to high contact-frequencies.
Original languageAmerican English
JournalPLoS Comput Biol
Issue number12
StatePublished - 2009


Dive into the research topics of 'Trade-off between positive and negative design of protein stability: from lattice models to real proteins'. Together they form a unique fingerprint.

Cite this