Deep-time consistency in proteome elemental composition across cellular and viral life

TL;DR

This study reveals that proteomes across all domains of life and viruses maintain a highly conserved elemental composition, indicating fundamental biochemical constraints that influenced the evolution of the amino acid alphabet.

Contribution

It demonstrates that elemental composition constraints are a core organizational principle of proteomes, independent of evolutionary lineage or function, and explores their origins through ancestral and synthetic proteomes.

Findings

Proteomes exhibit consistent elemental composition across diverse life forms.

Reduced primordial amino acid alphabets generate proteomes outside modern elemental constraints.

LUCA proteomes share the same elemental composition constraints as modern organisms.

Abstract

Proteins are constructed from a limited alphabet of ~20 amino acids, yet the origins and selection of this specific alphabet are unresolved. One largely overlooked aspect is whether elemental composition constrains the range of viable proteomes. Here, we analyze the elemental composition of thousands of proteomes spanning cellular domains and viral realms. Despite evolutionary divergence and orders-of-magnitude variation in proteome size and gene content, proteomes exhibit strikingly consistent elemental composition. This consistency is substantially more constrained than amino acid frequencies or physicochemical properties and is not explained by evolutionary relatedness, biological function, or amino acid usage alone. Viral proteomes occupy the same elemental composition space observed in cellular organisms despite the absence of a single viral common ancestor, suggesting common biochemical constraints shape proteome organization across life. To investigate the evolutionary origins of this pattern, we compare modern proteomes with multiple independent reconstructions of the Last Universal Common Ancestor (LUCA) and with synthetic reduced-alphabet proteomes generated from primordial amino acid alphabets. LUCA proteomes occupy the same constrained elemental composition space observed in modern Bacteria and Archaea, whereas reduced primordial-like alphabets systematically generated alternative elemental regimes outside the modern range despite retaining high sequence similarity to extant proteins. Reduced alphabets disrupt fold space and reorganize relationships between elemental composition and predicted protein structural organization. Our results suggest that constrained elemental composition represents a fundamental organizational property of proteomes, which emerged early in evolution and may have contributed to the selection and stabilization of the modern amino acid alphabet.