Structure-Function Mutational Analysis and Prediction of the Potential Impact of High Risk Non-Synonymous Single-Nucleotide Polymorphism on Poliovirus 2A Protease Stability Using Comprehensive Informatics Approaches
Polio viral proteinase 2A performs several essential functions in genome replication. Its inhibition prevents viral replication, thus making it an excellent substrate for drug development. In this study, the three-dimensional structure of 2A protease was determined and optimized by homology modellin...
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doaj-aa77354a62a347749def7086d021ed632020-11-24T22:25:32ZengMDPI AGGenes2073-44252018-04-019522810.3390/genes9050228genes9050228Structure-Function Mutational Analysis and Prediction of the Potential Impact of High Risk Non-Synonymous Single-Nucleotide Polymorphism on Poliovirus 2A Protease Stability Using Comprehensive Informatics ApproachesAmna Younus0Saba Munawar1Muhammad Faraz Bhatti2Aqsa Ikram3Faryal Mehwish Awan4Ishrat Jabeen5Nasar Virk6Hussnain Ahmed Janjua7Muhammad Arshad8Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Kashmir Highway, Islamabad 44000, PakistanResearch Center for Modeling and Simulation (RCMS), National University of Sciences and Technology (NUST), Sector H-12, Kashmir Highway, Islamabad 44000, PakistanAtta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Kashmir Highway, Islamabad 44000, PakistanAtta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Kashmir Highway, Islamabad 44000, PakistanAtta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Kashmir Highway, Islamabad 44000, PakistanResearch Center for Modeling and Simulation (RCMS), National University of Sciences and Technology (NUST), Sector H-12, Kashmir Highway, Islamabad 44000, PakistanAtta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Kashmir Highway, Islamabad 44000, PakistanAtta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Kashmir Highway, Islamabad 44000, PakistanDepartment of Bioinformatics and Biotechnology, International Islamic University, Sector H-10, Islamabad 44000, PakistanPolio viral proteinase 2A performs several essential functions in genome replication. Its inhibition prevents viral replication, thus making it an excellent substrate for drug development. In this study, the three-dimensional structure of 2A protease was determined and optimized by homology modelling. To predict the molecular basis of the interaction of small molecular agonists, docking simulations were performed on a structurally diverse dataset of poliovirus 2A protease (PV2Apr°) inhibitors. Docking results were employed to identify high risk missense mutations that are highly damaging to the structure, as well as the function, of the protease. Intrinsic disorder regions (IDRs), drug binding sites (DBS), and protein stability changes upon mutations were also identified among them. Our results demonstrated dominant roles for Lys 15, His 20, Cys 55, Cys 57, Cys 64, Asp 108, Cys 109 and Gly 110, indicating the presence of various important drug binding sites of the protein. Upon subjecting these sites to single-nucleotide polymorphism (SNP) analysis, we observed that out of 155 high risk SNPs, 139 residues decrease the protein stability. We conclude that these missense mutations can affect the functionality of the 2A protease, and that identified protein binding sites can be directed for the attachment and inhibition of the target proteins.http://www.mdpi.com/2073-4425/9/5/228poliovirus 2A protease (PV2Apr°)dockingsingle-nucleotide polymorphisms (SNPs)non-synonymous SNPs (nsSNPs)computational analysisdrug binding sitesstability changes |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Amna Younus Saba Munawar Muhammad Faraz Bhatti Aqsa Ikram Faryal Mehwish Awan Ishrat Jabeen Nasar Virk Hussnain Ahmed Janjua Muhammad Arshad |
spellingShingle |
Amna Younus Saba Munawar Muhammad Faraz Bhatti Aqsa Ikram Faryal Mehwish Awan Ishrat Jabeen Nasar Virk Hussnain Ahmed Janjua Muhammad Arshad Structure-Function Mutational Analysis and Prediction of the Potential Impact of High Risk Non-Synonymous Single-Nucleotide Polymorphism on Poliovirus 2A Protease Stability Using Comprehensive Informatics Approaches Genes poliovirus 2A protease (PV2Apr°) docking single-nucleotide polymorphisms (SNPs) non-synonymous SNPs (nsSNPs) computational analysis drug binding sites stability changes |
author_facet |
Amna Younus Saba Munawar Muhammad Faraz Bhatti Aqsa Ikram Faryal Mehwish Awan Ishrat Jabeen Nasar Virk Hussnain Ahmed Janjua Muhammad Arshad |
author_sort |
Amna Younus |
title |
Structure-Function Mutational Analysis and Prediction of the Potential Impact of High Risk Non-Synonymous Single-Nucleotide Polymorphism on Poliovirus 2A Protease Stability Using Comprehensive Informatics Approaches |
title_short |
Structure-Function Mutational Analysis and Prediction of the Potential Impact of High Risk Non-Synonymous Single-Nucleotide Polymorphism on Poliovirus 2A Protease Stability Using Comprehensive Informatics Approaches |
title_full |
Structure-Function Mutational Analysis and Prediction of the Potential Impact of High Risk Non-Synonymous Single-Nucleotide Polymorphism on Poliovirus 2A Protease Stability Using Comprehensive Informatics Approaches |
title_fullStr |
Structure-Function Mutational Analysis and Prediction of the Potential Impact of High Risk Non-Synonymous Single-Nucleotide Polymorphism on Poliovirus 2A Protease Stability Using Comprehensive Informatics Approaches |
title_full_unstemmed |
Structure-Function Mutational Analysis and Prediction of the Potential Impact of High Risk Non-Synonymous Single-Nucleotide Polymorphism on Poliovirus 2A Protease Stability Using Comprehensive Informatics Approaches |
title_sort |
structure-function mutational analysis and prediction of the potential impact of high risk non-synonymous single-nucleotide polymorphism on poliovirus 2a protease stability using comprehensive informatics approaches |
publisher |
MDPI AG |
series |
Genes |
issn |
2073-4425 |
publishDate |
2018-04-01 |
description |
Polio viral proteinase 2A performs several essential functions in genome replication. Its inhibition prevents viral replication, thus making it an excellent substrate for drug development. In this study, the three-dimensional structure of 2A protease was determined and optimized by homology modelling. To predict the molecular basis of the interaction of small molecular agonists, docking simulations were performed on a structurally diverse dataset of poliovirus 2A protease (PV2Apr°) inhibitors. Docking results were employed to identify high risk missense mutations that are highly damaging to the structure, as well as the function, of the protease. Intrinsic disorder regions (IDRs), drug binding sites (DBS), and protein stability changes upon mutations were also identified among them. Our results demonstrated dominant roles for Lys 15, His 20, Cys 55, Cys 57, Cys 64, Asp 108, Cys 109 and Gly 110, indicating the presence of various important drug binding sites of the protein. Upon subjecting these sites to single-nucleotide polymorphism (SNP) analysis, we observed that out of 155 high risk SNPs, 139 residues decrease the protein stability. We conclude that these missense mutations can affect the functionality of the 2A protease, and that identified protein binding sites can be directed for the attachment and inhibition of the target proteins. |
topic |
poliovirus 2A protease (PV2Apr°) docking single-nucleotide polymorphisms (SNPs) non-synonymous SNPs (nsSNPs) computational analysis drug binding sites stability changes |
url |
http://www.mdpi.com/2073-4425/9/5/228 |
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