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Factors stabilizing G:G W:H Cis base pair geometry in RNA crystal structuresAuthor: Jayanth Katuri Date: 2019-03-30 Report no: IIIT/TH/2019/25 Advisor:Abhijit Mitra AbstractNon-canonical base pairs are found to play a crucial role in folding of RNA molecules. Some of these non-canonical base pairs have been found to occur in nature in intrinsically unstable geometries. An understanding of how various interactions stabilize these base pairs will not only help in predicting higher order structures from secondary structures, but also provide insights into the sequence-structure function landscape of RNA molecules. One such intrinsically unstable non-canonical base pair is the G:G W:H Cis base pair, which converges to a stable G:G W:W Trans geometry when independently optimized using quantum mechanical (QM) methods. This study aims to uncover the external factors that stabilize this base pair using a combination of structural bioinformatics tools and QM methods. Such investigations were earlier used successfully to show that formation of higher order structures with external factors stabilized G:C W:W Trans base pair. Structural bioinformatics tools were used on a non-redundant set of 167 RNA crystal structures. G:G W:H Cis base pair was found to occur 123 times in this dataset. These occurrences of G:G W:H Cis base pair were categorized into 6 different environmental contexts. Environmental contexts are defined based on the external factors (other bases and metal ions) present in the vicinity of G:G W:H Cis base pairs,similar to the higher order structures identified in the study of G:C W:W Trans base pair. Quantum mechanics based geometry optimization calculations were performed on models, incorporating these environmental contexts at B3LYP level and using 6-31++(2d,2p) basis set to investigate the possible roles of these external factors towards stabilizing the geometry of this base pair. Interaction energies were calculated at MP2 level and using aug-cc-pVDZ basis set.The external factors that were found to stabilize the G:G W:H Cis base pair geometry are 1) Triplet formation by the guanine base G H , whose hoogstein edge is involved in G:G W:H Cis base pair, forming additional base pair with either adenine or cytosine through it’s watson crick edge, 2) Quartet formation of G:G W:H Cis base pair, with the G H base forming two additional base pairs, one with adenine though it’s sugar edge and the other with cytosine through it’s watson crick edge and 3) co-ordinate covalent bonds formed by Mg +2 cation with the O6 atoms of both the guanine bases. It is found that, in the absence of external factors, the G:G W:H Cis geometry is unstable even with two good hydrogen bonds and this could be due to the positioning the highly electronegative, and electron rich, O6 atoms closer to each other resulting in electrostatic repulsion. The aforementioned external factors hold the oxygen atoms together by 1) hydrogen bonds with hydrogen atoms of the exocyclic amino groups of the another partner base or 2) co-ordinate covalent bonds with metal ions which act like clamps, to maintain its observed crystal geometry. Full thesis: pdf Centre for Computational Natural Sciences and Bioinformatics |
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