Non-Isobaric Is Not Enough: Gap-Merge Safety for Unambiguous Peptide Readout
- 1Indian Institute of Management Kozhikode
Abstract
Selecting a set of non-isobaric amino acids is the standard way to guarantee unambiguous readout when peptide sequences are used to carry information. We show it is insufficient. Because tandem MS reads residues as differences between consecutive fragment masses, a single missing b/y ion merges two adjacent residues into one observed gap; if that merged gap aliases a single residue mass, the decoder does not register a dropout but emits one confident, wrong residue. Non-isobaricity cannot prevent this, because the colliding quantity is a sum rather than a residue. We formalize the missing condition—gap-merge safety, |m(a) +m(b)−m(c)| > τ for all a, b, c in the alphabet—as a decidable predicate with a machine-checked soundness proof in Lean 4, and characterize the collision structure of the proteinogenic alphabet exhaustively: beyond the Leu/Ile isobar and the Gln/Lys near-isobar, exactly two summed-gap collisions exist, Gly + Gly = Asn and Gly + Ala = Gln, making glycine disproportionately expensive. In simulation, alphabets satisfying gap-merge safety produce zero silent errors at every fragment dropout rate from 0 to 0.4, where alphabets chosen by non-isobaricity alone produce 1.0% to 6.9%; every failure becomes a detectable erasure rather than a silent substitution.
Related
- Comparative Assessment of Group Contribution Models for Estimating the Isobaric Heat Capacity of Ionic Liquids
- Isothermal-Isobaric Molecular Dynamics with a Foundation Interatomic Potential in LAMMPS across NVIDIA and Intel GPUs
- Transformer-inspired architectures make machine-learned electron densities accurate and transferable enough to bypass self-consistency
- Efficiency and Accessibility Are Not Enough: Chemical-Validity Filtering in High-Throughput Screening of Organic Photovoltaic Materials
- Writing and readout of luminescent defects on an optical nanofiber using an electron beam
BibTeX
@misc{bhogadi2026nonisobaric,
title = {{Non-Isobaric Is Not Enough: Gap-Merge Safety for Unambiguous Peptide Readout}},
author = {Laalini Bhogadi},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008527/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008527/v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Non-Isobaric Is Not Enough: Gap-Merge Safety for Unambiguous Peptide Readout
AU - Laalini Bhogadi
PY - 2026
DA - 2026/09/08
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008527/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008527/v1
AB - Selecting a set of non-isobaric amino acids is the standard way to guarantee unambiguous readout when peptide sequences are used to carry information. We show it is insufficient. Because tandem MS reads residues as differences between consecutive fragment masses, a single missing b/y ion merges two adjacent residues into one observed gap; if that merged gap aliases a single residue mass, the decoder does not register a dropout but emits one confident, wrong residue. Non-isobaricity cannot prevent this, because the colliding quantity is a sum rather than a residue. We formalize the missing condition—gap-merge safety, |m(a) +m(b)−m(c)| > τ for all a, b, c in the alphabet—as a decidable predicate with a machine-checked soundness proof in Lean 4, and characterize the collision structure of the proteinogenic alphabet exhaustively: beyond the Leu/Ile isobar and the Gln/Lys near-isobar, exactly two summed-gap collisions exist, Gly + Gly = Asn and Gly + Ala = Gln, making glycine disproportionately expensive. In simulation, alphabets satisfying gap-merge safety produce zero silent errors at every fragment dropout rate from 0 to 0.4, where alphabets chosen by non-isobaricity alone produce 1.0% to 6.9%; every failure becomes a detectable erasure rather than a silent substitution.
ER -