Molecular Dynamics Studies of Heterogeneous and Homogeneous Nucleic Acids and their Interaction with Proteins

Abstract

One of the main goals of modern biotechnology and biophysics is to understand the newlinestructure and interactions of biomolecules such as nucleic acids and proteins. The complexity newlinein understanding the living systems and the processes occurring in them primarily revolves newlinearound these biomolecules. Understanding the molecular level details of such processes is newlinedifficult and is not always possible using experimental methods. Computational methods newlineprove to be efficient alternative tools in studying the atomistic details of molecular processes. newlineMolecular dynamics (MD) simulation is one such method that is extremely used to study newlinestructure-function relationships of biomolecules. newlineThe present thesis has two parts: heterogeneous nucleic acids and homogeneous newlinenucleic acids. The heterogeneous nucleic acids include DNA-RNA hybrids, locked nucleic newlineacids and 2 -O-methyl modified duplexes that have a wide range of applications in nucleic newlineacid-based therapies. Extensive analyses of MD trajectories suggest that the structural and newlineenergetic properties of DNA-RNA hybrids depend on the extent of mixing of base newlinecomposition in their DNA strand. However, such variations were not seen in their RNA newlinestrand. The MD simulation results also showed that the decreasing deoxypyrimidine newlinecomposition in DNA strand leads to transformation of the DNA-RNA hybrid conformation newlinefrom A-type to A/B-type. The possible factors responsible for the inactivity of ribonuclease H newline(RNase H) enzyme towards hybrids with high deoxypyrimidine composition have also been newlineproposed. Thermodynamic stabilities of the duplexes were explained by using binding free newlineenergies. Next, investigations have been carried out to understand the interactions between newlinernase H enzyme with the DNA-RNA hybrid and the energy cost accompanying the complex newlineformation. The binding of enzyme to the nucleic acid induces conformational transitions newlinetowards N-type or S-type in deoxyribose sugars that are important for efficient binding. Since this enzyme exhibit close structural and functional similarity