Prof. Deva Priyakumar (IIIT-Hyderabad, India)
Tuesday 05 June
11:00 - 12:00
Urea is a chemical denaturant that assists protein unfolding and shifts the folding equilibrium towards the unfolded state. While a number of studies that attempted to understand the molecular mechanism of this phenomenon have been reported during the last three decades, a general consensus is lacking. It has been experimentally shown that among all the functional groups in proteins, urea interacts strongly with the aromatic groups. The nature of the interactions between urea and aromatic groups which makes it more stable than those involving urea and polar groups was not understood. The presentation will discuss our attempts at providing structural, thermodynamic and kinetic basis of these novel interactions. Free energy calculations on the unfolding of Trp-cage miniprotein reveal the importance of urea-aromatic interactions in the unfolding process. The primary mode of interaction between the two is shown to be stacking interactions in addition to hydrogen bonded and NH-π interactions. This was further quantified by thermodynamic integration and quantum mechanical calculations. Lifetime calculations based on µs long MD simulations reveal these to be long lasting in the ps timescales.
We further show that stacking type interactions between urea and aromatic groups have significant role to play in urea transporters, damaged DNA with urea lesions and in drug-receptor interactions. All the three structures of urea transporters that have been solved so far, aromatic residues line the selectivity pore of the channel. We show using umbrella sampling free energy calculations that favourable urea-aromatic interactions are directly responsible for the ability of these transporters to discriminate from other molecules for transport across cell membranes. Such stacking interactions lower the barrier for the transportation of urea (compared to other molecules) to pass through the selectivity filter.
DNA damage is a process by which the nucleobases are chemically modified which lead to hostile repercussions. One of the most common damage, thymine glycol has been shown to sometimes undergo hydrolysis to form urea moiety in the DNA. We show that such DNA molecules with such urea lesions are able to maintain their structural integrity because of their ability to form hydrogen bonding and stacking interactions just like the nucleobases. We will also present a database analysis of all protein structures to which urea or urea derivatives are bound from the protein databank. It is found that statistically significant number of instances where urea and one of the aromatic amino acid side chains are involved in stacking interaction. In summary, we will present the role of novel and unusual stacking interaction between urea and aromatic in different facets in biology and the possible role of these interactions in increasing the binding affinity/specificity of drug-receptor interactions.
 Goyal, S.; Chattopadhyay, A.; Kasavajhala, K.; Priyakumar, U. D. J. Am. Chem. Soc. 2017, 139, 14931.
 Padhi, S.; Priyakumar, U. D. J. Chem. Theor. Comput. 2016, 12, 5190.
 Suresh, G.; Padhi, S.; Patil, I.; Priyakumar, U. D. Biochemistry 2016, 55, 5653.