DESIGN OF PROTEINS WITH SELECTED THERMAL-PROPERTIES

Background: Methods of model protein design have until now been largel y ad hoc, yielding sequences that are foldable only at some seemingly arbitrary simulation temperature. But real proteins exist and must fol d within an imposed thermal environment. The need exists for a sequenc e design method based on statistical-mechanical first principles, thus containing a rigorous treatment of folding temperature. Results: In t his work, we report a method of rational sequence design that takes a target structure and a desired optimal folding temperature T-Z and gen erates a sequence that is predicted to be thermodynamically stable wit h respect to the target structure at a folding temperature T-F approxi mate to T-Z. This 'cumulant design method' is based on a mean-field hi gh temperature expansion of the molecular partition function. Folding simulations of the designed sequences confirm that sequences designed at T-Z do indeed fold optimally when T-F approximate to T-Z. Conclusio ns: The cumulant method is highly successful in designing model protei ns, It also provides some insight into the thermal properties of real proteins, illuminating the features that distinguish thermostable and psychrotropic (cold-loving) sequences from their mesophilic counterpar ts. (C) Current Biology Ltd