Mathematical model of a short translatable G-quadruplex and an assessment of its relevance to misfolding-induced proteostasis

Siddhartha Kundu; Siddhartha Kundu

doi:10.3934/mbe.2020135

Mathematical Biosciences and Engineering

2020, Volume 17, Issue 3: 2470-2493. doi: 10.3934/mbe.2020135

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Research article

Mathematical model of a short translatable G-quadruplex and an assessment of its relevance to misfolding-induced proteostasis

Siddhartha Kundu ^,

Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, INDIA

Received: 17 November 2019 Accepted: 14 February 2020 Published: 25 February 2020

G-quadruplexes can form in protein coding and non-coding segments such as the untranslated regions and introns of the mRNA transcript of several genes. This implies that amino acid forms of the G-quadruplex may have important consequences for protein homeostasis and the diseases caused by their alterations thereof. However, the absence of a suitable model and multitude of predicted physical forms has precluded a comprehensive enumeration and analysis of potential translatable G-quadruplexes. In this manuscript a mathematical model of a short translatable G-quadruplex (TG4) in the protein coding segment of the mRNA of a hypothetical gene is presented. Several novel indices (α, β) are formulated and utilized to categorize and select codons along with the amino acids that they code for. A generic algorithm is then iteratively deployed which computes the entire complement of peptide members that TG4 corresponds to, i.e., PTG4~TG4. The presence, distribution and relevance of this peptidome to protein sequence is investigated by comparing it with disorder promoting short linear motifs. In frame termination codon, co-occurrence, homology and distribution of overlapping/shared amino acids suggests that TG4 (~PTG4) may facilitate misfolding-induced proteostasis. The findings presented rigorously argue for the existence of a unique and potentially clinically relevant peptidome of a short translatable G-quadruplex that could be used as a diagnostic- or prognostic-screen of certain proteopathies.
- algorithm,
- codon,
- G-quadruplex,
- peptidome,
- misfolding induced proteopathy,
- translatable G-quadruplex
Citation: Siddhartha Kundu. Mathematical model of a short translatable G-quadruplex and an assessment of its relevance to misfolding-induced proteostasis[J]. Mathematical Biosciences and Engineering, 2020, 17(3): 2470-2493. doi: 10.3934/mbe.2020135

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Abstract

G-quadruplexes can form in protein coding and non-coding segments such as the untranslated regions and introns of the mRNA transcript of several genes. This implies that amino acid forms of the G-quadruplex may have important consequences for protein homeostasis and the diseases caused by their alterations thereof. However, the absence of a suitable model and multitude of predicted physical forms has precluded a comprehensive enumeration and analysis of potential translatable G-quadruplexes. In this manuscript a mathematical model of a short translatable G-quadruplex (TG4) in the protein coding segment of the mRNA of a hypothetical gene is presented. Several novel indices (α, β) are formulated and utilized to categorize and select codons along with the amino acids that they code for. A generic algorithm is then iteratively deployed which computes the entire complement of peptide members that TG4 corresponds to, i.e., PTG4~TG4. The presence, distribution and relevance of this peptidome to protein sequence is investigated by comparing it with disorder promoting short linear motifs. In frame termination codon, co-occurrence, homology and distribution of overlapping/shared amino acids suggests that TG4 (~PTG4) may facilitate misfolding-induced proteostasis. The findings presented rigorously argue for the existence of a unique and potentially clinically relevant peptidome of a short translatable G-quadruplex that could be used as a diagnostic- or prognostic-screen of certain proteopathies.

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