Lipid-Driven Biophysical Selection of β-Furanoside-5'-Phosphate as the Sole Scaffold of Extant RNA

Abstract

The emergence of RNAs primordial backbone presents a fundamental question in the study of lifes origins: why was {beta}-furanoside-5-phosphate selected over other isomeric alternatives as the predominant building block during the origin of life? In contrast to previous studies that have demonstrated selective synthetic routes to canonical RNA structures, we explore biophysical factors that selectively favor {beta}-furanoside and 5-nucleotide over their undesired isomers. Inspired by the chromatographic elution order of nucleoside and nucleotide isomers, we establish a new selection model to discriminate between them. {beta}-Furanoside is found to be more lipid-permeable than any other configurational isomer, making it the most abundant species after permeation. Outward permeation selectively screens intracellularly formed nucleotides, enriching 5-nucleotide as the primary RNA building block within a protocell. The unique properties of representative canonical nucleosides and nucleotides are rationalized based on both their structural and dynamic characteristics, as elucidated by DFT and MD calculations. A scenario in which {beta}-furanoside selectively accumulates in a lipid droplet is further investigated using a specifically designed micromixer. Together, these findings suggest the existence of a primitive selection mechanism driven by purely biophysical forces, which may have played a critical role in advancing key steps in the progression of primitive biomolecules.