Molecular dynamics simulations in designing DARPins as phosphorylation-specific protein binders of ERK2
Extracellular signal-regulated kinases 1 and 2 (ERK1/2) play key roles in promoting cell survival and proliferation through the phosphorylation of various substrates. Remarkable antitumour activity is found in many inhibitors that act upstream of the ERK pathway. However, drug-resistant tumour cells...
Saved in:
Main Authors: | , , , , |
---|---|
Format: | Article |
Published: |
MDPI
2021
|
Subjects: | |
Online Access: | http://eprints.um.edu.my/27975/ |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
id |
my.um.eprints.27975 |
---|---|
record_format |
eprints |
spelling |
my.um.eprints.279752022-06-22T07:47:55Z http://eprints.um.edu.my/27975/ Molecular dynamics simulations in designing DARPins as phosphorylation-specific protein binders of ERK2 Gautam, Vertika Nimmanpipug, Piyarat Zain, Sharifuddin Md Abd Rahman, Noorsaadah Lee, Vannajan Sanghiran QD Chemistry QH301 Biology Extracellular signal-regulated kinases 1 and 2 (ERK1/2) play key roles in promoting cell survival and proliferation through the phosphorylation of various substrates. Remarkable antitumour activity is found in many inhibitors that act upstream of the ERK pathway. However, drug-resistant tumour cells invariably emerge after their use due to the reactivation of ERK1/2 signalling. ERK1/2 inhibitors have shown clinical efficacy as a therapeutic strategy for the treatment of tumours with mitogen-activated protein kinase (MAPK) upstream target mutations. These inhibitors may be used as a possible strategy to overcome acquired resistance to MAPK inhibitors. Here, we report a class of repeat proteins-designed ankyrin repeat protein (DARPin) macromolecules targeting ERK2 as inhibitors. The structural basis of ERK2-DARPin interactions based on molecular dynamics (MD) simulations was studied. The information was then used to predict stabilizing mutations employing a web-based algorithm, MAESTRO. To evaluate whether these design strategies were successfully deployed, we performed all-atom, explicit-solvent molecular dynamics (MD) simulations. Two mutations, Ala -> Asp and Ser -> Leu, were found to perform better than the original sequence (DARPin E40) based on the associated energy and key residues involved in protein-protein interaction. MD simulations and analysis of the data obtained on these mutations supported our predictions. MDPI 2021-08 Article PeerReviewed Gautam, Vertika and Nimmanpipug, Piyarat and Zain, Sharifuddin Md and Abd Rahman, Noorsaadah and Lee, Vannajan Sanghiran (2021) Molecular dynamics simulations in designing DARPins as phosphorylation-specific protein binders of ERK2. Molecules, 26 (15). ISSN 1420-3049, DOI https://doi.org/10.3390/molecules26154540 <https://doi.org/10.3390/molecules26154540>. 10.3390/molecules26154540 |
institution |
Universiti Malaya |
building |
UM Library |
collection |
Institutional Repository |
continent |
Asia |
country |
Malaysia |
content_provider |
Universiti Malaya |
content_source |
UM Research Repository |
url_provider |
http://eprints.um.edu.my/ |
topic |
QD Chemistry QH301 Biology |
spellingShingle |
QD Chemistry QH301 Biology Gautam, Vertika Nimmanpipug, Piyarat Zain, Sharifuddin Md Abd Rahman, Noorsaadah Lee, Vannajan Sanghiran Molecular dynamics simulations in designing DARPins as phosphorylation-specific protein binders of ERK2 |
description |
Extracellular signal-regulated kinases 1 and 2 (ERK1/2) play key roles in promoting cell survival and proliferation through the phosphorylation of various substrates. Remarkable antitumour activity is found in many inhibitors that act upstream of the ERK pathway. However, drug-resistant tumour cells invariably emerge after their use due to the reactivation of ERK1/2 signalling. ERK1/2 inhibitors have shown clinical efficacy as a therapeutic strategy for the treatment of tumours with mitogen-activated protein kinase (MAPK) upstream target mutations. These inhibitors may be used as a possible strategy to overcome acquired resistance to MAPK inhibitors. Here, we report a class of repeat proteins-designed ankyrin repeat protein (DARPin) macromolecules targeting ERK2 as inhibitors. The structural basis of ERK2-DARPin interactions based on molecular dynamics (MD) simulations was studied. The information was then used to predict stabilizing mutations employing a web-based algorithm, MAESTRO. To evaluate whether these design strategies were successfully deployed, we performed all-atom, explicit-solvent molecular dynamics (MD) simulations. Two mutations, Ala -> Asp and Ser -> Leu, were found to perform better than the original sequence (DARPin E40) based on the associated energy and key residues involved in protein-protein interaction. MD simulations and analysis of the data obtained on these mutations supported our predictions. |
format |
Article |
author |
Gautam, Vertika Nimmanpipug, Piyarat Zain, Sharifuddin Md Abd Rahman, Noorsaadah Lee, Vannajan Sanghiran |
author_facet |
Gautam, Vertika Nimmanpipug, Piyarat Zain, Sharifuddin Md Abd Rahman, Noorsaadah Lee, Vannajan Sanghiran |
author_sort |
Gautam, Vertika |
title |
Molecular dynamics simulations in designing DARPins as phosphorylation-specific protein binders of ERK2 |
title_short |
Molecular dynamics simulations in designing DARPins as phosphorylation-specific protein binders of ERK2 |
title_full |
Molecular dynamics simulations in designing DARPins as phosphorylation-specific protein binders of ERK2 |
title_fullStr |
Molecular dynamics simulations in designing DARPins as phosphorylation-specific protein binders of ERK2 |
title_full_unstemmed |
Molecular dynamics simulations in designing DARPins as phosphorylation-specific protein binders of ERK2 |
title_sort |
molecular dynamics simulations in designing darpins as phosphorylation-specific protein binders of erk2 |
publisher |
MDPI |
publishDate |
2021 |
url |
http://eprints.um.edu.my/27975/ |
_version_ |
1738510683001061376 |
score |
13.160551 |