Design of Proteins with Specified Thermal Properties

Original · EN

We propose a new and effective means for designing stable and fast-folding polypeptide sequences using a cumulant expansion of the molecular partition function. This method is unique in that TZ, the ``cumulant design temperature'' entered as a parameter in the design process, is predicted also to be the optimal folding temperature. The method was tested using monte-carlo folding simulations of the designed sequences, at various folding temperatures TF. (Folding simulations were run on a cubic lattice for computational convenience, but the design process itself is lattice-independent.) Simulations confirmed that, over a wide range of TZ, all designed sequences folded rapidly when TF ≈ TZ. Additionally, highly thermostable model proteins were created simply by designing with high TZ. The mechanism proposed in these studies provides a plausible pathway for the evolutionary design of biologically active proteins, which must fold and remain stable within a relatively narrow range of temperatures.