Research Projects

How are evolutionary selected functional and conformational features imprinted on the sequence, and how does Nature introduce multi-functionality into proteins through minimal changes in primary sequence? Is functional promiscuity compromised in going from a disordered domain to a well-folded structure? 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 these structural energetic subtleties at both local and global level be interwoven to design protein-based nano-sensors? We plan to answer these questions by studying homologous proteins that display extremes of disorder tendency and promiscuity – one completely unstructured, promiscuous and exhibiting weak DNA-binding (CytR) and the other well-folded, displaying specific and strong DNA-binding (LacR). CytR folds upon binding DNA to a structure resembling LacR.We therefore plan to construct a mutational path from the disordered CytR to the ordered LacR through rational protein design, extensive ensemble spectroscopic characterization, and DNA-binding assays. The connection between patterning of amino-acids, structure and functional promiscuity gleaned from this approach would then be exploited (together with a simple model) to design protein-based versatile sensors that can rapidly detect minor changes in ambient conditions and report them via reliable spectral signatures.