Faculty of 1000 Review

Rational design of proteins that exchange on functional timescales.
Davey JA, Damry AM, Goto NK, Chica RA
Nat Chem Biol. 2017 Dec; 13(12):1280-1285

Reviewed by Lynn Kamerlin, Uppsala University, Uppsala, Sweden and Yashraj Kulkarni, Uppsala University, Uppsala, Sweden.

NEW FINDING | TECHNICAL ADVANCE DOI: 10.3410/f.732025541.793540058
Although many in silico protein design efforts have been made to improve the functional characteristics of proteins, there has been less focus on incorporating the regulation of protein dynamics into the design process. This article introduces a novel method called meta-multistate design (meta-MSD), which attempts to plug the gaps pertaining to dynamics in current computational protein design (CPD) approaches. Specifically, it predicts protein sequences that can spontaneously change their conformations between predefined states. Here, the authors describe an interesting approach to predicting the static and dynamic natures of proteins by identifying the number and stability of conformational states in which a certain protein sequence can exist. Streptococcal protein G domain β1 has been used for validating the method. In this protein, W43 was chosen as a target residue to design the conformational exchange between the "buried" and "solvent-accessible" states along with a transition state that would occur at functional timescales. The designed proteins showed an exchange of folds, the barrier to which was also estimated. meta-MSD has been presented as a method that can push the frontiers of CPD with respect to designing functionally diverse proteins. This is an important development considering that there is increasing evidence for the fact that altered conformational dynamics can significantly affect the function of a protein. Therefore, it can propel more effective design approaches to obtain proteins that function more efficiently, thereby resembling their natural counterparts.