Introducing the PARCH Scale for Quantifying the Hydropathy of Nucleic Acids and Nucleic Acid–Protein Complexes

Hydropathy studies have been extensively conducted for proteins, offering valuable insights into their structure and functionality. However, there is far less understanding of the hydropathy associated with the tertiary and quaternary structures of nucleic acids─such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA)─and their interactions with proteins. In this work, we extend our recently developed Protocol for Assigning a Residue’s Character on a Hydropathy (PARCH) scale to nucleic acids and nucleic acid–protein complexes. The PARCH scale quantifies the hydropathy of each nucleic acid residue based on its chemical identity and topographical features. The PARCH analysis for both DNA and RNA reveals that the backbone, consisting of phosphate and sugar atoms, is significantly more hydrophilic than the nucleotide bases; backbone PARCH values are an order of magnitude higher than those of the bases. In DNA, distortions from the organized double-helical structure, such as base flipping or altered base pairing, increase the hydropathy values. With its greater structural complexity, RNA exhibits a broader range of hydropathy values than DNA, reflecting its increased interaction with water. Thus, based on the PARCH values, RNA is more hydrophilic than DNA on average. PARCH analysis of DNA–protein and RNA–protein complexes reveals intricate binding patterns, including interactions between charged amino acid residues and the hydrophilic nucleic acid backbone, as well as hydrophobic patches on proteins engaging with the hydrophobic grooves of nucleic acid bases. These findings highlight the potential of PARCH analysis to provide valuable insights into the underlying principles of nucleic acid–protein interactions. The PARCH scale shows promise as a useful tool for advancing the development of functional RNA and DNA fragments for future therapeutic applications.