Abstract

The relationship between nucleic acid (NA) sequence, structure and function is intricately connected to the stabilizing interactions (primarily hydrogen bonding and 1t-stacking) that occur between the monomeric subunits that constitute NAs. Therefore, detailed insights into the. nature of the stabilizing interactions would permit the full exploitation of the structure-function relationship in NAs. A complete understanding of the role of the stabilizing interactions in NAs involves the fulfillment of two requirements: 1) The ability to determine the electronic structure of the monomeric units (in terms of the electron density distribution as an observable) that make up the fundamental structure of NAs, which is possible through the use of quantum chemical calculations, and 2) The ability to characterize the electronic structure of these monomeric units in the context of realistic NA structures. Ideally, such molecular structures are determined experimentally. These two ideas are combined into a methodology that has been designed, tested and validated in the work presented here. The proof of concept culminates in the ability of the methodology to exploit the structure-function relationship in NAs through procurement of full stabilization profiles of host NA and guest (small molecule inhibitors to the function of the NA) complexes, where the potential inhibitors were designed on the basis of the stabilization profiles of the host and natural ligand complexes