Structural Characteristics of PON1 with Leu55Met and Gln192Arg Variants Influencing Oxidative-Stress-Related Diseases: An Integrated Molecular Modeling and Dynamics Study
<i>Background and Objectives</i>: PON1 is a multi-functional antioxidant protein that hydrolyzes a variety of endogenous and exogenous substrates in the human system. Growing evidence suggests that the Leu55Met and Gln192Arg substitutions alter PON1 activity and are linked with a variety...
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MDPI AG
2023-11-01
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| Online Access: | https://www.mdpi.com/1648-9144/59/12/2060 |
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| author | Sudhan M. Janakiraman V. Sheikh F. Ahmad Sabry M. Attia Talha Bin Emran Rajesh B. Patil Shiek S. S. J. Ahmed |
| author_facet | Sudhan M. Janakiraman V. Sheikh F. Ahmad Sabry M. Attia Talha Bin Emran Rajesh B. Patil Shiek S. S. J. Ahmed |
| author_sort | Sudhan M. |
| collection | DOAJ |
| description | <i>Background and Objectives</i>: PON1 is a multi-functional antioxidant protein that hydrolyzes a variety of endogenous and exogenous substrates in the human system. Growing evidence suggests that the Leu55Met and Gln192Arg substitutions alter PON1 activity and are linked with a variety of oxidative-stress-related diseases. <i>Materials and Methods:</i> We implemented structural modeling and molecular dynamics (MD) simulation along with essential dynamics of PON1 and molecular docking with their endogenous (n = 4) and exogenous (n = 6) substrates to gain insights into conformational changes and binding affinity in order to characterize the specific functional ramifications of PON1 variants. <i>Results:</i> The Leu55Met variation had a higher root mean square deviation (0.249 nm) than the wild type (0.216 nm) and Gln192Arg (0.202 nm), implying increased protein flexibility. Furthermore, the essential dynamics analysis confirms the structural change in PON1 with Leu55Met vs. Gln192Arg and wild type. Additionally, PON1 with Leu55Met causes local conformational alterations at the substrate binding site, leading to changes in binding affinity with their substrates. <i>Conclusions:</i> Our findings highlight the structural consequences of the variants, which would increase understanding of the role of PON1 in the pathogenesis of oxidative-stress-related diseases, as well as the management of endogenous and exogenous chemicals in the treatment of diseases. |
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| issn | 1010-660X 1648-9144 |
| language | English |
| last_indexed | 2024-03-08T20:33:21Z |
| publishDate | 2023-11-01 |
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| series | Medicina |
| spelling | doaj.art-270456e6298e4be6a7424ae434b3acf32023-12-22T14:23:40ZengMDPI AGMedicina1010-660X1648-91442023-11-015912206010.3390/medicina59122060Structural Characteristics of PON1 with Leu55Met and Gln192Arg Variants Influencing Oxidative-Stress-Related Diseases: An Integrated Molecular Modeling and Dynamics StudySudhan M.0Janakiraman V.1Sheikh F. Ahmad2Sabry M. Attia3Talha Bin Emran4Rajesh B. Patil5Shiek S. S. J. Ahmed6Drug Discovery and Multi-Omics Laboratory, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam 603103, Tamil Nadu, IndiaDrug Discovery and Multi-Omics Laboratory, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam 603103, Tamil Nadu, IndiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, USADepartment of Pharmaceutical Chemistry, Sinhgad Technical Education Societys, Sinhgad College of Pharmacy, Vadgaon (BK), Pune 411041, Maharashtra, IndiaDrug Discovery and Multi-Omics Laboratory, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam 603103, Tamil Nadu, India<i>Background and Objectives</i>: PON1 is a multi-functional antioxidant protein that hydrolyzes a variety of endogenous and exogenous substrates in the human system. Growing evidence suggests that the Leu55Met and Gln192Arg substitutions alter PON1 activity and are linked with a variety of oxidative-stress-related diseases. <i>Materials and Methods:</i> We implemented structural modeling and molecular dynamics (MD) simulation along with essential dynamics of PON1 and molecular docking with their endogenous (n = 4) and exogenous (n = 6) substrates to gain insights into conformational changes and binding affinity in order to characterize the specific functional ramifications of PON1 variants. <i>Results:</i> The Leu55Met variation had a higher root mean square deviation (0.249 nm) than the wild type (0.216 nm) and Gln192Arg (0.202 nm), implying increased protein flexibility. Furthermore, the essential dynamics analysis confirms the structural change in PON1 with Leu55Met vs. Gln192Arg and wild type. Additionally, PON1 with Leu55Met causes local conformational alterations at the substrate binding site, leading to changes in binding affinity with their substrates. <i>Conclusions:</i> Our findings highlight the structural consequences of the variants, which would increase understanding of the role of PON1 in the pathogenesis of oxidative-stress-related diseases, as well as the management of endogenous and exogenous chemicals in the treatment of diseases.https://www.mdpi.com/1648-9144/59/12/2060paraoxonasevariantoxidative stressmolecular dockingstructural modelinglactones |
| spellingShingle | Sudhan M. Janakiraman V. Sheikh F. Ahmad Sabry M. Attia Talha Bin Emran Rajesh B. Patil Shiek S. S. J. Ahmed Structural Characteristics of PON1 with Leu55Met and Gln192Arg Variants Influencing Oxidative-Stress-Related Diseases: An Integrated Molecular Modeling and Dynamics Study Medicina paraoxonase variant oxidative stress molecular docking structural modeling lactones |
| title | Structural Characteristics of PON1 with Leu55Met and Gln192Arg Variants Influencing Oxidative-Stress-Related Diseases: An Integrated Molecular Modeling and Dynamics Study |
| title_full | Structural Characteristics of PON1 with Leu55Met and Gln192Arg Variants Influencing Oxidative-Stress-Related Diseases: An Integrated Molecular Modeling and Dynamics Study |
| title_fullStr | Structural Characteristics of PON1 with Leu55Met and Gln192Arg Variants Influencing Oxidative-Stress-Related Diseases: An Integrated Molecular Modeling and Dynamics Study |
| title_full_unstemmed | Structural Characteristics of PON1 with Leu55Met and Gln192Arg Variants Influencing Oxidative-Stress-Related Diseases: An Integrated Molecular Modeling and Dynamics Study |
| title_short | Structural Characteristics of PON1 with Leu55Met and Gln192Arg Variants Influencing Oxidative-Stress-Related Diseases: An Integrated Molecular Modeling and Dynamics Study |
| title_sort | structural characteristics of pon1 with leu55met and gln192arg variants influencing oxidative stress related diseases an integrated molecular modeling and dynamics study |
| topic | paraoxonase variant oxidative stress molecular docking structural modeling lactones |
| url | https://www.mdpi.com/1648-9144/59/12/2060 |
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