Inosine Nucleobase Acts as Guanine in Interactions with Protein Side Chains

Abstract

A central intermediate in purine catabolism, the inosine nucleobase hypoxanthine is also one of the most abundant modified nucleobases in RNA and plays key roles in the regulation of gene expression and determination of cell fate. It is known that hypoxanthine acts as guanine when interacting with other nucleobases and base pairs most favorably with cytosine. However, its preferences when it comes to interactions with amino acids remain unknown. Here we present for the first time the absolute binding free energies and the associated interaction modes between hypoxanthine and all standard, non-glycyl/non-prolyl amino acid side chain analogs as derived from molecular dynamics simulations and umbrella sampling in high- and low-dielectric environments. We illustrate the biological relevance of the derived affinities by providing a quantitative explanation for the specificity of hypoxanthine-guanine phosphoribosyltransferase, a key enzyme in the purine salvage pathway. Our results demonstrate that in its affinities for protein side chains, hypoxanthine closely matches guanine, much more so than its precursor adenine.

Frameshifting preserves key physicochemical properties of proteins

“…Sequences including noncanonical amino acids or nucleotides were not analyzed. The majority of the amino acid property scales studied were extracted from the AAindex database (42,43), and were complemented by additional consensus scales derived by Atchley et al (29) and an additional category of recently derived nucleobase affinity scales (44)(45)(46)(47). The frameshifted variants of individual protein sequences were generated by removing the first four bases (+1 shift) or the first two bases (resulting in the −1 shift) in their wild-type mRNA coding sequences and translating them using the universal genetic code.…”

Non-bulky Lesions in Human DNA: The Ways of Formation, Repair, and Replication

“…Eukaryotic Pols incorporate dAMP opposite uracil, resulting in GC→AT transversions in the subsequent replication rounds ( Table ) [ 60 ]. Furthermore, dCMP is preferentially incorporated opposite hypoxanthine, causing the AT→GC transversion [ 61 - 63 ]. Xanthine and oxanine form hydrogen bonds with thymine, thereby causing GC→AT transversions during replication [ 64 ].…”

Multipurpose and Durable Adhesive Hydrogel Assisted by Adenine and Uracil from Ribonucleic Acid

“…Nucleobase recognition has been widely utilised for fabricating materials with promising performance. RNA, a single‐strand nucleic acid polymer, has a critical task of translating and transferring genetic information into various proteins . The specific nucleobase recognition of gene expression is achieved through forming base pairs, including adenine‐uracil (A‐U) and guanine‐cytosine (G‐C) .…”

“…RNA, as ingle-strand nucleic acid polymer,h as ac ritical task of translatinga nd transferring genetic information into various proteins. [22][23][24] The specific nucleobase recognition of gene expression is achieved throughf orming base pairs, including adenine-uracil (A-U) and guanine-cytosine (G-C). [25][26][27] Nucleobase pairs of A-U from RNA have drawn much attention for fabricatingv arious materials, such as polymer films, [28] organic light-emitting devices, [29] supramolecular micelles [30] and hydrogels.…”