Design of proteins with selected thermal properties.
BACKGROUND
Methods of model protein design have until now been largely ad hoc, yielding sequences that are foldable only at some seemingly arbitrary simulation temperature. But real proteins exist and must fold within an imposed thermal environment. The need exists for a sequence design method based on statistical-mechanical first principles, thus containing a rigorous treatment of folding temperature.


RESULTS
In this work, we report a method of rational sequence design that takes a target structure and a desired optimal folding temperature TZ and generates a sequence that is predicted to be thermodynamically stable with respect to the target structure at a folding temperature TF approximately TZ. This 'cumulant design method' is based on a mean-field high temperature expansion of the molecular partition function. Folding simulations of the designed sequences confirm that sequences designed at TZ do indeed fold optimally when TF approximately TZ.


CONCLUSIONS
The cumulant method is highly successful in designing model proteins. It also provides some insight into the thermal properties of real proteins, illuminating the features that distinguish thermostable and psychotropic (cold-loving) sequences from their mesophilic counterparts.
Morrissey
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MP
Division of Applied Sciences, Harvard University, Cambridge, MA 02138, USA.
Shakhnovich
E I
EI
D000818:Animals; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry*; D017421:Sequence Analysis; D013696:Temperature
D011506:Proteins