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Abstract

De novo gene emergence, increasingly being recognised as a biologically relevant pro- cess, provides a route for new proteins to be formed from previously non-coding DNA. Proteins born in this way are considered as random sequences, and typically assumed to lack defined structure. While it remains unclear how likely a de novo protein is to as- sume a soluble and stable tertiary structure, intersecting evidence from random-sequence and de novo designed proteins suggests that native-like biophysical properties are abun- dant in sequence space. In addition, laboratory evolution has shown random proteins to be highly evolvable with respect to diverse properties. Using sets of putative de novo proteins previously identified in human and fly, we here characterise a library of these sequences in vitro to assess their solubility and structure propensity. Bioinformatic com- parison to a library of random proteins with no evolutionary history suggests that de novo proteins may have remarkably similar bulk properties (such as secondary structure and disorder content) to unevolved random sequences of a given length and amino acid composition. However, upon expression in vitro, de novo proteins exhibit higher intrinsic solubility which can be further induced by the DnaK chaperone system. We therefore suggest that, while random sequence proteins are a useful proxy for de novo proteins in terms of structure propensity, de novo proteins could be better integrated in the cellular system than their random counterparts. Their greater solubility indicates that de novo proteins have been shaped by their brief evolutionary histories, and further implies that de novo proteins may be more evolvable than synthetic random sequences.