The effect of amino acid repertoire on protein structure and function

To understand protein structure emergence is to comprehend the evolutionary transition from messy chemistry to the first heritable molecular systems. Early proteins were probably flexible in structure, promiscuous in activity and ambiguous in sequence. Moreover, first sequences were presumably composed of prebiotically plausible amino acids from endogenous and exogenous sources which form only a subset of the extant protein alphabet. Here we investigate the effect of most recent additions to the amino acid alphabet on protein structure/function relationship and the properties of random proteins as the evolutionary point-zero for the earliest sequences as well as for proteins emerging de novo from the non-coding parts of the genome. Random or never born proteins are of a special interest for the contemporary biology as they unveil the unexposed side of the protein sequence space. We constructed an in silico library of random proteins with the natural amino acid alphabet, analyzed its structure/disorder/aggregation content and selected 45 sequences for subsequent experimental preparation and biophysical characterization. We observed that structure content in random sequence space does not differ significantly from the natural proteins. However, the analyses of the aggregation propensity showed a..