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Vemuri Saurabh –  A QM-based insight

Vemuri Saurabh received his MS Dual Degree in  Computational Natural Sciences (CNS). His research work was supervised by Prof. Abhijit Mitra. Here’s a summary of his research work on On the diverse roles of Class II nucleobase protonation in shaping structures and functions of RNA base pairs – a QM-based insight:

RNA is a versatile biopolymer. Different RNAs build up the protein synthesis machinery in living organisms. Non-protein coding RNAs often participate in gene regulation, catalysis of biochemical reactions, and many other cellular processes. The efficiency of functional RNAs depends on their accurate folding into compact three-dimensional structures. RNAs are composed of only four types of nucleotides having similar chemical properties. So, the sources of structural complexity observed in these folded RNAs remain ambiguous. Instead, hydrogen-bonded planar RNA base pairs have the potential to be the fundamental building block of RNA. They display remarkable diversities in their geometries, stabilities, and physicochemical properties. Properties of RNA base pairs are strongly influenced by nucleobase modification, such as post-transcriptional changes, tautomerization, ionization, etc. One such important modification is nucleobase protonation. Protonation at different polar sites of nucleobases are associated with positive free energy change. However, protonation-induced modifications to nucleobases result in subsequent stabilizing interactions, which compensate for the thermodynamic cost of protonation. For example, protonation converts a hydrogen bond acceptor to a hydrogen bond donor and therefore opens up new base-pairing opportunities through the protonated edge of the nucleobase (Class I). In other cases, the protonation-induced changes may influence the stability of the base pairs formed through the unprotonated edges of the base (Class II). Instances of Class II protonation in RNA bases is nontrivial to detect for both experiments and in-silico techniques, as the loaded proton does not form any inter-base hydrogen bonds. Hence, the contribution of Class II protonation in determining RNA’s structure and function remains majorly unexplored. Recently a strategy has been proposed to study the consequences of Class II protonation on the geometry and stability of RNA base pairs [1]. It involves comparing the electronic structure properties of the different base pairs optimized with and without the Class II protonation. In the past, this method revealed that Class II protonation at the N7 and N3 positions of guanine stabilizes different RNA base pairs, which are intrinsically unstable. In this work, the same strategy is applied to explore the consequences of Class II protonation at the N3 position of guanine and N3 & N7 positions of adenine on the geometry and stability of different RNA base pairs. Those are the sites where the thermodynamic cost of protonation is higher than other sites. Analysis of RNA crystal structure datasets and electronic structure calculations carried out at DFT and DFT-D levels reveal a number of interesting insights. In general, it is observed that charge redistribution caused by Class II protonation alters the hydrogen bonding potential at the polar sites located on the unprotonated edges of nucleobases. Such changes collectively determine the geometry and stability of the base pairs formed through the unprotonated edges. A set of RNA base pairs are reported which are sensitive to Class II type nucleobase protonation and hence have putative biotechnological application in pH sensing. 

 References: [1] A. Halder, S. Bhattacharya, A. Datta, D. Bhattacharyya, and A. Mitra, “The role of N7 protonation of guanine in determining the structure, stability and function of RNA base pairs,” Physical Chemistry Chemical Physics, vol. 17, pp. 26 249–26 263, 2015. [Online]. Available: http://dx.doi.org/10.1039/C5CP04894J