Exploring the sequence space of unknown oligomers and polymers

The characterization of the chemistry of life on earth has been facilitated by developments in analysis and sequencing of bio-oligomers using tandem mass spectrometry (MS/MS). Bio-oligomers can be identified with sequence-level resolution in analytes more complex than any synthetic mixture, enabled by well-established knowledge of fragmentation properties and extensive MS/MS databases built up over decades. However, unknown oligomer systems remain difficult to characterize, as no comparable databases exist, partly because of the vast chemical diversity and fragmentation pathways. Here, we present oligomer-soup-sequencing (OLIGOSS), a new approach to the sequencing of unknown oligomer systems. Using a novel set of backbone-agnostic abstract properties to define fragmentation, OLIGOSS is capable of sequencing any linear oligomer class amenable to MS/MS, regardless of backbone chemistry. We validated OLIGOSS by sequencing synthetic peptides, polyesters, polyimines and depsipeptide oligomers, mapped RNA methylation sites, and a ribosomally synthesized peptide, thioholgamide, directly from a cell lysate without purification.