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Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA Polymerase β’s activity

DNA polymerase ß is a 39 kDa enzyme that is a major component of Base Excision Repair in human cells. The enzyme comprises two major domains, a 31 kDa domain responsible for the polymerase activity and an 8 kDa domain, which bind ssDNA and has a deoxyribose phosphate (dRP) lyase activity. DNA polyme...

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Main Authors: Homouz, D., Tan, K. H. Joyce, Shamsir, M. Shahir, Moustafa, I. M., Idriss, H. T.
Format: Article
Language:English
Published: Elsevier Inc. 2018
Subjects:
Q Science (General)
Online Access:http://eprints.utm.my/id/eprint/81810/1/DirarMohammadAlHomouz2018_MolecularDynamicsSimulationsSuggestChanges.pdf
http://eprints.utm.my/id/eprint/81810/
http://dx.doi.org/10.1016/j.jmgm.2018.08.007
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spelling my.utm.818102019-09-29T08:13:08Z http://eprints.utm.my/id/eprint/81810/ Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA Polymerase β’s activity Homouz, D. Tan, K. H. Joyce Shamsir, M. Shahir Moustafa, I. M. Idriss, H. T. Q Science (General) DNA polymerase ß is a 39 kDa enzyme that is a major component of Base Excision Repair in human cells. The enzyme comprises two major domains, a 31 kDa domain responsible for the polymerase activity and an 8 kDa domain, which bind ssDNA and has a deoxyribose phosphate (dRP) lyase activity. DNA polymerase ß was shown to be phosphorylated in vitro with protein kinase C (PKC) at serines 44 and 55 (S44 and S55), resulting in loss of its polymerase enzymic activity, but not its ability to bind ssDNA. In this study, we investigate the potential phosphorylation-induced structural changes for DNA polymerase ß using molecular dynamics simulations. The simulations show drastic conformational changes of the polymerase structure as a result of S44 phosphorylation. Phosphorylation-induced conformational changes transform the closed (active) enzyme structure into an open one. Further analysis of the results points to a key hydrogen bond and newly formed salt bridges as potential drivers of these structural fluctuations. The changes observed with S55/44 and S55 phosphorylation were less dramatic and the integrity of the H-bond was not compromised. Thus the phosphorylation of S44 is the major contributor to structural fluctuations that lead to loss of enzymatic activity. Elsevier Inc. 2018 Article PeerReviewed application/pdf en http://eprints.utm.my/id/eprint/81810/1/DirarMohammadAlHomouz2018_MolecularDynamicsSimulationsSuggestChanges.pdf Homouz, D. and Tan, K. H. Joyce and Shamsir, M. Shahir and Moustafa, I. M. and Idriss, H. T. (2018) Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA Polymerase β’s activity. Journal of Molecular Graphics and Modelling, 84 . pp. 236-241. ISSN 1093-3263 http://dx.doi.org/10.1016/j.jmgm.2018.08.007 DOI:10.1016/j.jmgm.2018.08.007
institution Universiti Teknologi Malaysia
building UTM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Teknologi Malaysia
content_source UTM Institutional Repository
url_provider http://eprints.utm.my/
language English
topic Q Science (General)
spellingShingle Q Science (General)
Homouz, D.
Tan, K. H. Joyce
Shamsir, M. Shahir
Moustafa, I. M.
Idriss, H. T.
Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA Polymerase β’s activity
description DNA polymerase ß is a 39 kDa enzyme that is a major component of Base Excision Repair in human cells. The enzyme comprises two major domains, a 31 kDa domain responsible for the polymerase activity and an 8 kDa domain, which bind ssDNA and has a deoxyribose phosphate (dRP) lyase activity. DNA polymerase ß was shown to be phosphorylated in vitro with protein kinase C (PKC) at serines 44 and 55 (S44 and S55), resulting in loss of its polymerase enzymic activity, but not its ability to bind ssDNA. In this study, we investigate the potential phosphorylation-induced structural changes for DNA polymerase ß using molecular dynamics simulations. The simulations show drastic conformational changes of the polymerase structure as a result of S44 phosphorylation. Phosphorylation-induced conformational changes transform the closed (active) enzyme structure into an open one. Further analysis of the results points to a key hydrogen bond and newly formed salt bridges as potential drivers of these structural fluctuations. The changes observed with S55/44 and S55 phosphorylation were less dramatic and the integrity of the H-bond was not compromised. Thus the phosphorylation of S44 is the major contributor to structural fluctuations that lead to loss of enzymatic activity.
format Article
author Homouz, D.
Tan, K. H. Joyce
Shamsir, M. Shahir
Moustafa, I. M.
Idriss, H. T.
author_facet Homouz, D.
Tan, K. H. Joyce
Shamsir, M. Shahir
Moustafa, I. M.
Idriss, H. T.
author_sort Homouz, D.
title Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA Polymerase β’s activity
title_short Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA Polymerase β’s activity
title_full Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA Polymerase β’s activity
title_fullStr Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA Polymerase β’s activity
title_full_unstemmed Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA Polymerase β’s activity
title_sort molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits dna polymerase β’s activity
publisher Elsevier Inc.
publishDate 2018
url http://eprints.utm.my/id/eprint/81810/1/DirarMohammadAlHomouz2018_MolecularDynamicsSimulationsSuggestChanges.pdf
http://eprints.utm.my/id/eprint/81810/
http://dx.doi.org/10.1016/j.jmgm.2018.08.007
_version_ 1651866365090332672
score 13.211869

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