Dataset Information

Computational SNP Analysis and Molecular Simulation Revealed the Most Deleterious Missense Variants in the NBD1 Domain of Human ABCA1 Transporter.

ABSTRACT: The ATP-binding cassette transporter A1 (ABCA1) is a membrane-bound exporter protein involved in regulating serum HDL level by exporting cholesterol and phospholipids to load up in lipid-poor ApoA-I and ApoE, which allows the formation of nascent HDL. Mutations in the ABCA1 gene, when presents in both alleles, disrupt the canonical function of ABCA1, which associates with many disorders related to lipid transport. Although many studies have reported the phenotypic effects of a large number of ABCA1 variants, the pathological effect of non-synonymous polymorphisms (nsSNPs) in ABCA1 remains elusive. Therefore, aiming at exploring the structural and functional consequences of nsSNPs in ABCA1, in this study, we employed an integrated computational approach consisting of nine well-known in silico tools to identify damaging SNPs and molecular dynamics (MD) simulation to get insights into the magnitudes of the damaging effects. In silico tools revealed four nsSNPs as being most deleterious, where the two SNPs (G1050V and S1067C) are identified as the highly conserved and functional disrupting mutations located in the NBD1 domain. MD simulation suggested that both SNPs, G1050V and S1067C, changed the overall structural flexibility and dynamics of NBD1, and induced substantial alteration in the structural organization of ATP binding site. Taken together, these findings direct future studies to get more insights into the role of these variants in the loss of the ABCA1 function.

SUBMITTER: Dash R

PROVIDER: S-EPMC7589834 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Computational SNP Analysis and Molecular Simulation Revealed the Most Deleterious Missense Variants in the NBD1 Domain of Human ABCA1 Transporter.

Dash Raju R Ali Md Chayan MC Rana Md Liton ML Munni Yeasmin Akter YA Barua Largess L Jahan Israt I Haque Mst Fatema MF Hannan Md Abdul MA Moon Il Soo IS

International journal of molecular sciences 20201014 20

The ATP-binding cassette transporter A1 (ABCA1) is a membrane-bound exporter protein involved in regulating serum HDL level by exporting cholesterol and phospholipids to load up in lipid-poor ApoA-I and ApoE, which allows the formation of nascent HDL. Mutations in the <i>ABCA1</i> gene, when presents in both alleles, disrupt the canonical function of ABCA1, which associates with many disorders related to lipid transport. Although many studies have reported the phenotypic effects of a large numbe ...[more]

PMID: 33066695

Similar Datasets

Project description:BACKGROUND:Although synonymous single nucleotide variants (sSNVs) do not alter the protein sequences, they have been shown to play an important role in human disease. Distinguishing pathogenic sSNVs from neutral ones is challenging because pathogenic sSNVs tend to have low prevalence. Although many methods have been developed for predicting the functional impact of single nucleotide variants, only a few have been specifically designed for identifying pathogenic sSNVs. RESULTS:In this work, we describe a computational model, IDSV (Identification of Deleterious Synonymous Variants), which uses random forest (RF) to detect deleterious sSNVs in human genomes. We systematically investigate a total of 74 multifaceted features across seven categories: splicing, conservation, codon usage, sequence, pre-mRNA folding energy, translation efficiency, and function regions annotation features. Then, to remove redundant and irrelevant features and improve the prediction performance, feature selection is employed using the sequential backward selection method. Based on the optimized 10 features, a RF classifier is developed to identify deleterious sSNVs. The results on benchmark datasets show that IDSV outperforms other state-of-the-art methods in identifying sSNVs that are pathogenic. CONCLUSIONS:We have developed an efficient feature-based prediction approach (IDSV) for deleterious sSNVs by using a wide variety of features. Among all the features, a compact and useful feature subset that has an important implication for identifying deleterious sSNVs is identified. Our results indicate that besides splicing and conservation features, a new translation efficiency feature is also an informative feature for identifying deleterious sSNVs. While the function regions annotation and sequence features are weakly informative, they may have the ability to discriminate deleterious sSNVs from benign ones when combined with other features. The data and source code are available on website http://bioinfo.ahu.edu.cn:8080/IDSV .

Dataset Information

Computational SNP Analysis and Molecular Simulation Revealed the Most Deleterious Missense Variants in the NBD1 Domain of Human ABCA1 Transporter.

Publications

Computational SNP Analysis and Molecular Simulation Revealed the Most Deleterious Missense Variants in the NBD1 Domain of Human ABCA1 Transporter.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets