Decoding the Complexity of Nucleic Acids: Computational Approaches Across Multiscale Levels

In response to the growing interest within the scientific community, there has been an increasing commitment to the study of nucleic acids in recent years. Correlations have been identified between their properties and several pathological conditions, and there is considerable promise for the utilization of these systems in innovative pharmaceutical applications. In light of the contemporary scientific significance and the state of the art of computational methods for these biopolymers, the present thesis endeavors to address the challenges in the theoretical modeling of such systems using a multiscale approach. Initially, insights concerning the hydrolysis reaction were obtained from model molecules describing the backbone of nucleic acids. Subsequently, an investigation was conducted into the stability of nucleobases to assess the efficacy of computational approaches in predicting genome damage. These results provide a basis for evaluating the efficacy of quantum mechanics methods. Finally, alchemical free energy calculations were used to characterize a complete sequence binding behavior. Consequently, this study is a notable instance of effective nucleic acid modeling through the application of molecular mechanics. The preceding theoretical framework enabled the investigation of a protein-nucleic acid complex. The system was thoroughly characterized, and the resulting data was capable of elucidating subtle mechanisms implicated in the onset and progression of diseases and aging. Additionally, the role of machine learning in this context was investigated by assessing the capability of a recently developed machine learning code in predicting the folding of a short sequence. This thesis constitutes a comprehensive study of the current level of achievement in the field of computational modeling of nucleic acids. Through these efforts, the effectiveness of these approaches in the characterization of the processes involving these molecules was substantiated.