Research SummaryTowards designing tunable nano-machines: Taking advantage of protein disorder
How are evolutionary selected functional features imprinted on the structure and how does Nature introduce multi-functionality into proteins through minimal changes in the primary sequence? Can a quantitative picture of the interplay between energetic frustration, folding speed, stability and functional constraints be detailed at the amino-acid level on homologous proteins? How can an understanding of these structural-energetic subtleties at both local and global level be interwoven to design protein-based nano-machines?
We plan to answer these questions by studying homologous proteins that display extremes of conformational behavior – one completely unstructured, promiscuous and exhibiting weak DNA-binding (CytR) and the other well-folded, displaying specific and strong DNA-binding (LacR) - through rational protein engineering and positive/negative design, extensive biophysical characterization and DNA-binding assays. We will be guided by a simple Ising-like statistical mechanical model that incorporates diverse physical terms in its energy function apart from the extracted folding-functional landscape of the different mutant proteins. Combining the model and experiments, we expect to develop a robust predictive approach that can aid in designing proteins that can bind specific DNA sequences, sense changes in ambient environment, and exhibit enhanced mutational and thermal fitness.
Figure Legend: Deciphering the Sequence-Function Code