Staff View: Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA polymerase β activity

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

DNA polymerase β 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, Dirar, Tan, Joyce Kwee Hong, Shamsir, Mohd. Shahir, Moustafa, Ibrahim M., Idriss, Haitham T.
Format:	Article
Published:	Elsevier Inc. 2018
Subjects:	QH301 Biology TP Chemical technology
Online Access:	http://eprints.utm.my/id/eprint/85466/ http://dx.doi.org/10.1016/j.jmgm.2018.08.007
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spelling	my.utm.854662020-06-30T08:56:37Z http://eprints.utm.my/id/eprint/85466/ Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA polymerase β activity Homouz, Dirar Tan, Joyce Kwee Hong Shamsir, Mohd. Shahir Moustafa, Ibrahim M. Idriss, Haitham T. QH301 Biology TP Chemical technology DNA polymerase β 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 β 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 β 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. 2018-09 Article PeerReviewed Homouz, Dirar and Tan, Joyce Kwee Hong and Shamsir, Mohd. Shahir and Moustafa, Ibrahim M. and Idriss, Haitham T. (2018) Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA polymerase β 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/
topic	QH301 Biology TP Chemical technology
spellingShingle	QH301 Biology TP Chemical technology Homouz, Dirar Tan, Joyce Kwee Hong Shamsir, Mohd. Shahir Moustafa, Ibrahim M. Idriss, Haitham T. Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA polymerase β activity
description	DNA polymerase β 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 β 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 β 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, Dirar Tan, Joyce Kwee Hong Shamsir, Mohd. Shahir Moustafa, Ibrahim M. Idriss, Haitham T.
author_facet	Homouz, Dirar Tan, Joyce Kwee Hong Shamsir, Mohd. Shahir Moustafa, Ibrahim M. Idriss, Haitham T.
author_sort	Homouz, Dirar
title	Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA polymerase β activity
title_short	Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA polymerase β activity
title_full	Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA polymerase β activity
title_fullStr	Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA polymerase β activity
title_full_unstemmed	Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA polymerase β activity
title_sort	molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits dna polymerase β activity
publisher	Elsevier Inc.
publishDate	2018
url	http://eprints.utm.my/id/eprint/85466/ http://dx.doi.org/10.1016/j.jmgm.2018.08.007
_version_	1672610538104815616
score	13.211869

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

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