Research Projects

How are evolutionary selected functional and conformational featuresimprinted on the sequence, and how does Nature introduce multi-functionalityinto proteins through minimal changes in primary sequence? Is functionalpromiscuity compromised in going from a disordered domain to a well-foldedstructure? Can a quantitative picture of the interplay between energeticfrustration, folding speed, stability and functional constraints be detailed atthe amino-acid level on homologous proteins? How can these structural energetic subtleties at both local and global level be interwoven to designprotein-based nano-sensors?We plan to answer these questions by studying homologous proteins thatdisplay extremes of disorder tendency and promiscuity – one completelyunstructured, promiscuous and exhibiting weak DNA-binding (CytR) and theother well-folded, displaying specific and strong DNA-binding (LacR). CytRfolds upon binding DNA to a structure resembling LacR.We therefore plan toconstruct a mutational path from the disordered CytR to the ordered LacRthrough rational protein design, extensive ensemble spectroscopiccharacterization, and DNA-binding assays. The connection betweenpatterning of amino-acids, structure and functional promiscuity gleaned fromthis approach would then be exploited (together with a simple model) todesign protein-based versatile sensors that can rapidly detect minor changesin ambient conditions and report them via reliable spectral signatures.

1) Identified the origins of disorder in an intrinsically disordered protein 2) Engineered order from disorder 3) Salt-sensitivity of DNA-binding proteins explained 4) A novel method to quantify binding isotherms with a simplistic model 5) Origins of collapse transition in a disordered protein and the associated binding heterogeneity 6) First report of excited folded-like conformation in a disordered ensemble 7) First accurate measurement of absolute heat capacity of IDPs