Hypothesis of the Peptide Protocode and the Directed Emergence of the Nucleotide Code

The origin of the genetic code remains one of the most challenging questions in the study of life. The classical “RNA world” model assumes that nucleotides were the first carriers of information and catalysis, yet this scenario encounters a severe combinatorial paradox: the probability of functional ribozymes or genes arising by chance is exceedingly small. Here we advance an alternative hypothesis: the earliest coding framework originated from amino acid assemblies rather than nucleotides. Amino acid conglomerates—and subsequently short peptides—could spontaneously self‑organize into stable motifs through conformational selection, thereby generating functional structures. We define this process as a peptide protocode, a primordial mapping of amino acids into functional motifs that preceded the canonical genetic code. Importantly, peptide aggregates provided binding environments that stabilized nucleotides, granting them sufficient residence time to escape random fluctuations and polymerize into ordered chains. This perspective reframes the origin of coding not as a contingent accident but as a directed outcome of intrinsic molecular organization. Our quantitative analysis indicates that blind combinatorial search is infeasible within the age of the Universe, whereas directed peptide‑guided assembly offers a realistic pathway for the emergence of coding systems, thereby providing a new perspective on the origin of life.