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Author Spotlight: In Silico Creation and Impact of Carbonylated Amino Acids on Protein Structure and Function
Published on: April 26, 2024
In silico study of colchicine resistance molecular mechanisms caused by tubulin structural polymorphism
Harutyun Sahakyan1, Narek Abelyan1,2, Vahram Arakelov1,2
1Department of Bioengineering, Bioinformatics and Molecular Biology, Russian-Armenian University, Yerevan, Armenia.
Abstract:
Starting from 1972, colchicine is known as the most useful drug for prevention of familial Mediterranean fever attacks. However, some patients do not respond to colchicine treatment, even taken in high doses. Despite the fact, that different hypotheses have been proposed, the molecular mechanisms of colchicine resistance are not completely clear. It is generally known, that colchicine binds β-tubulin and inhibits microtubules polymerization. The β-tubulin gene has SNPs, which lead to amino acid substitutions, and some of them are located in colchicine binding site (CBS). We have assumed, that this SNPs can affect tubulin-colchicine interaction and might be the reason for colchicine resistance. With this in mind, we modeled 7 amino acid substitutions in CBS, performed molecular dynamics simulations of tubulin-colchicine complex and calculated binding energies for every amino acid substitution. Thus, our study shows, that two amino acid substitutions in the β-tubulin, namely A248T and M257V, reduce binding energy for approximately 2-fold. Based on this, we assume, that these amino acid substitutions could be the reason for colchicine resistance. Thus, our study gives a new insight into colchicine resistance mechanism and provides information for designing colchicine alternatives, that could be effective for colchicine resistant patients.
Insights
Colchicine resistance in familial Mediterranean fever may stem from specific β-tubulin gene variations. Two identified amino acid substitutions significantly reduce colchicine binding, offering new insights into treatment failure.
Area of Science:
- Pharmacology
- Genetics
- Molecular Biology
Background:
- Colchicine has been the primary treatment for familial Mediterranean fever (FMF) since 1972.
- A subset of FMF patients exhibit resistance to colchicine, even at high dosages.
- The precise molecular mechanisms underlying colchicine resistance remain incompletely understood.
Purpose of the Study:
- To investigate the potential role of single nucleotide polymorphisms (SNPs) in the β-tubulin gene in colchicine resistance.
- To model and analyze the impact of specific β-tubulin amino acid substitutions on colchicine binding affinity.
Main Methods:
- Computational modeling of seven amino acid substitutions within the colchicine binding site (CBS) of β-tubulin.
- Molecular dynamics simulations were employed to analyze the tubulin-colchicine complex.
- Calculation of binding energies for each modeled amino acid substitution.
Main Results:
- Two specific amino acid substitutions in β-tubulin, A248T and M257V, were identified.
- These substitutions were shown to reduce the binding energy of colchicine to β-tubulin by approximately 50%.
- The findings suggest a direct link between these genetic variations and diminished drug efficacy.
Conclusions:
- Specific amino acid substitutions in the β-tubulin colchicine binding site may explain colchicine resistance in FMF patients.
- This research provides novel insights into the molecular basis of colchicine resistance.
- The results can inform the development of alternative therapeutic strategies for colchicine-resistant FMF.
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