PROF. N. YATHINDRA

Nature’s selection of 3’,5’ links vis-a-vis 2’,5’ links in nucleic acids to encode genetic information is intriguing. 2’,5’ links are formed in abundance and serve as a template in non-enzymatic reactions indicating that they might have been the ancestors of the biotic 3’,5’ links, which could have evolved from a pool of 3’,5’ and 2’,5’ links. Biological systems do use 2’,5’ links during intron splicing and in interferon treated cells. It has been our endeavor to decipher stereochemistry, polymorphism and topological properties of 2’,5’ DNA and 2’,5’ RNA duplexes to obtain insights from a stereochemical perspective for Nature’s choice of 3’,5’scaffold. We have shown that shapes and dimensions of the repeating nucleotides of 3’,5’ and 2’,5’ isomers bear in inverse relationship and a preference for a non BDNA like duplex for 2’,5’DNA with constraints for base pair movements suggesting lack of topological flexibility in 2’,5’DNA duplexes. We suggest that optimization of both duplex stability and helix topology must have been guiding factors for settling the chemical etiology of nucleic acids.

Modeling the structures of RNases H and their substrate complexes towards design of inhibitors

RNases Hs are ubiquitous enzymes involved in the removal of RNA primer from the (RNA.DNA) chimeric duplex during DNA replication and play a crucial role in the antisense strategy of gene regulation. RNases H I, abundant in bacteria, shares the same fold as in RNases H II, predominant in eukarya, except for the compact C terminal lobe. While no sequence similarity exists between the RNases H I and RNases II, considerable sequence resemblance is present within each family. Comparative analysis of RNases H I and RNases H II sequences and structural features across the genomes, and molecular dynamics simulations of these two enzymes and their substrate complexes are being carried out to identify common critical features of binding and recognition of the substrate to obtain insights towards the design of inhibitors.

New insights into DNA triplex structures and DNA triplex bending

DNA triplexes are formed by both isomorphic (structurally alike) and nonisomorphic (structurally dissimilar) base triplets. We have shown that (i) the base triplet non-isomorphism may be articulated in structural terms by a residual twist (∆tº), and the difference in base triplet radius (∆r Å), and (ii) their influence on DNA triplex is largely mechanistic, leading to the prediction of a high (t+∆t)º and low (t-∆t)º twist at the successive steps of a parallel or an antiparallel triplex. Efficacy of this concept is corroborated by molecular dynamics (MD) simulation of a number of parallel and antiparallel DNA triplexes comprising alternating non-isomorphic base triplets. We have also shown that base triplet non-isomorphism causes DNA triplexes into exhibiting sequence dependent non-uniform conformation which may be relevant in deciphering the specificity of interaction with DNA triplex binding proteins. Further, it has been found for the first time that nonisomorphic base triplets induce bending in DNA triplexes.