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Horizontal detection of post-translational modifications to an amino acid with a nanopore based on analyte volume and translocation-time

A method is proposed for the detection of post-translational modifications (PTMs) in single amino acids (AAs) for three types of PTMs (methylation, acetylation, and phosphorylation). It is preceded by a precursor step in which the terminal residue cleaved from a peptide is identified with a set of transfer RNAs (tRNAs) in a method proposed earlier (doi: 10.36227/techrxiv.19318145.v3). The identified AA (unmodified or modified) is separated from its cognate tRNA and translocated through a nanopore under electrophoresis. The resulting current blockade level (a proxy for analyte volume) and its width (a proxy for analyte translocation time) are measured and used to identify any PTM that might be present. The theoretical volumes of the 20 proteinogenic AAs and their PTMs are computed from crystallographic data and the ratio of the volume of a modified AA to that of an unmodified one obtained. The theoretical translocation time for the 20 AAs and their PTMs through a nanopore with a bilevel voltage profile is calculated with a Fokker-Planck drift-diffusion model. A 2-D scatter plot with these two quantities is generated for each AA type. Experimentally measured blockade levels and widths for an AA, modified or unmodified, can now be compared with the AA’s scatter plot to assign a PTM for a modified AA. PTM assignment is horizontal across the PTMs for the AA because the latter has already been identified from its cognate tRNA in the precursor step, the other 19 AA types and their PTMs are not involved. Computational results are presented for 49 PTMs covering all 20 AAs and the three PTM types mentioned above.