Session 1B: Inaugural Lectures by Fellows/Associates

Kalidas Sen

Misfolding and intrinsic disorder: When a protein fails to fold

Folding of proteins is crucial for executing cellular functions. Protein folding/misfolding relies on the concept of a rugged funnel-shaped energy landscape with the native state located at the global free energy minimum. The ruggedness in the energy landscape ensures that in addition to this global minimum, there are many local minima that correspond to partial/total misfolded states. Experimental techniques also confirm such a diverse conformational manifold under native conditions. There is equilibrium between the native state and several partially folded conformations which constitute the native state ensemble. Folding or refolding to such misfolded conformations may lead to a change in the functionality or off-pathway aggregation and causes a range of diseases or loss of protein functions. Intrinsically disordered proteins do not fold into well-defined native structures and exist in nature as a fluctuating ensemble of interconvertible conformations under standard physiological conditions. These functional proteins are aggregation-prone and are implicated in many neurodegenerative diseases and some forms of cancer. The speaker’s group probed the underlying physical principles that govern misfolding and intrinsic disorder in proteins via theoretical and computational methods. The results provide insights into the effects of environment, sequence composition, mutations, hydration, structural flexibility, and foldability of these proteins.