Molecular Modelling and Evaluation of Hidden Information in ABCB11 Gene Mutations

Abstract

Background: Cholestatic disorders are divided in the extra and intra-hepatic that created due to the severe liver diseases. ABCB11 encodes the bile salt export pump and this gene is mutated in several forms of intrahepatic cholestasis. So far, some molecular features of this gene was studies.

Objective: Using a developed web server, we identified high number of rare codons in this gene, and four cases were related to BSEP-deficient patients which can be used for drug design.

Material and methods: By in-silico modelling of ABCB11, some of rare codons in different locations of ATP8b1 gene were identified and evaluated. Using several web servers a number of mutations that converted non-rare codons to rare codon in these patients were identified.

Results: Some of these rare Codons were located at special positions by mutation of which, the new side chains do not seem suitable for protein structure and function. Furthermore, this mutation changed the protein folding rate that may have a critical role in proper folding. Thus, primary change of these codons contributes to BSEP deficiency.

Conclusion: This work is a comprehensive analysis of rare codons of ABCB11 and assessment of a number of these rare codon in protein levels. Rare codons evaluation can enhance our understanding of ABCB11 structural protein of ABCB11, and help us to develop mutation-specific therapies in design of new drugs.

Keywords: Bioinformatics Analysis; Mutation; Rare Codon; ABCB11.

Figure1

The ribbon diagram of BSEP protein modelled in I-TSSAR Web Servers.

Figure2

Schematic representation of the rare (orange) and highly rare (red) codons in ABCB11gene.

Figure3

Representation the rare codon of Arg, Leu, Ile, and Pro in the ABCB11 gene. These residues display in red, blue, green, orange, and red, respectively.

Figure4

The representation of RCCs location in ABCB11 gene using MSS algorithm (A), minmax algorithm (B), and sliding window method (C).

Figure5

Schematic representation of the codon usage of ABCB11 gene and position of rare codons and mutations, highlighted in yellow and red, respectively.

Figure6

A) the ribbon diagram of BSEP protein, with location of Arg⁴¹⁵ residue (rare codon). The Arg415⁴¹⁵residue forms the hydrogen bond with Gln⁴¹⁴ B) mutation Arg⁴¹⁵ to Gln⁴¹⁵.

Figure7

A) the ribbon representation of BSEP protein, with location of Arg⁴³² residue (rare codon). B) Mutation of Arg⁴³² to Thr⁴³².

Figure8

A) the ribbon diagram of BSEP protein, with location of Arg⁴⁷⁰ residue (rare codon). The Arg⁴⁷⁰ residue forms the hydrogen bond with Asp⁴⁷³ B) mutation Arg⁴⁷⁰ to Gln⁴⁷⁰.

Figure9

A) The ribbon diagram of BSEP protein, with location of Leu¹²⁴² residue (rare codon). B) Mutation of Leu¹²⁴² to Ile¹²⁴².

Figure10

A) The ribbon diagram of BSEP protein, with location of Ser⁵³⁹ residue. B) mutation Ser⁵³⁹ to Arg⁵³⁹ (rare codon). C) The ribbon diagram of BSEP protein, with location of Thr⁸⁵⁹ residue. D) mutation Thr⁸⁵⁹ to Arg⁸⁵⁹ (rare codon). E) The ribbon diagram of BSEP protein, with location of Gly⁹⁸² residue. F) Mutation Gly⁹⁸² to Arg⁹⁸² (rare codon). G) The ribbon diagram of BSEP protein, with location of Gly¹¹¹⁶ residue. H) Mutation Gly¹¹¹⁶ to Arg¹¹¹⁶ (rare codon).