Near-Native Entangled Protein Conformations are the Molecular Bridge Connecting Synonymous Mutations to Long-Timescale Changes in Protein Structure and Function

Synonymous mutations, which alter an mRNA sequence but not the encoded protein sequence, has been found to long-timescale function of proteins, including specific activity enzymes and ability proteins form oligomers. It is unknown how synonymous mutations lead such changes in structure function, why these altered structures are fixed by proteostasis machinery. Here, we address this gap our knowledge using a combination multi-scale molecular modeling, high-throughput simulations, meta-analysis literature. We first show that across E. coli cytosolic proteome many nascent populate subpopulations long-lived kinetically trapped states near native like likely have reduced functionality due localized misfolding. then show, coarse-grained near-native misfolded can bypass chaperones because they expose similar hydrophobic surface area as state. demonstrate, through experimental literature, vitro it common for appreciable be misfolded, non-functional chaperones. Finally, demonstrate population shifts entangled brought about explain resulting proteins. These studies indicate there fourth fate cells - near-native, soluble machinery whose populations influenced translation elongation speed. results motivate future efforts search structures, influence ‘dark proteome’ on cells.