Generating a conformational landscape of ubiquitin chains at atomistic resolution by back-mapping based sampling
Ubiquitin chains are flexible multidomain proteins that have important biological functions in cellular signalling. Computational studies with all-atom molecular dynamics simulations of the conformational spaces of polyubiquitins can be challenging due to the system size and a multitude of long-live...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2022.1087963/full |
| _version_ | 1797956540387295232 |
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| author | Simon Hunkler Teresa Buhl Oleksandra Kukharenko Christine Peter |
| author_facet | Simon Hunkler Teresa Buhl Oleksandra Kukharenko Christine Peter |
| author_sort | Simon Hunkler |
| collection | DOAJ |
| description | Ubiquitin chains are flexible multidomain proteins that have important biological functions in cellular signalling. Computational studies with all-atom molecular dynamics simulations of the conformational spaces of polyubiquitins can be challenging due to the system size and a multitude of long-lived meta-stable states. Coarse graining is an efficient approach to overcome this problem—at the cost of losing high-resolution details. Recently, we proposed the back-mapping based sampling (BMBS) approach that reintroduces atomistic information into a given coarse grained (CG) sampling based on a two-dimensional (2D) projection of the conformational landscape, produces an atomistic ensemble and allows to systematically compare the ensembles at the two levels of resolution. Here, we apply BMBS to K48-linked tri-ubiquitin, showing its applicability to larger systems than those it was originally introduced on and demonstrating that the algorithm scales very well with system size. In an extension of the original BMBS we test three different seeding strategies, i.e. different approaches from where in the CG landscape atomistic trajectories are initiated. Furthermore, we apply a recently introduced conformational clustering algorithm to the back-mapped atomistic ensemble. Thus, we obtain insight into the structural composition of the 2D landscape and illustrate that the dimensionality reduction algorithm separates different conformational characteristics very well into different regions of the map. This cluster analysis allows us to show how atomistic trajectories sample conformational states, move through the projection space and in sum converge to an atomistic conformational landscape that slightly differs from the original CG map, indicating a correction of flaws in the CG template. |
| first_indexed | 2024-04-10T23:51:36Z |
| format | Article |
| id | doaj.art-a5ddac889b394ae08a5b507f2a91b574 |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-04-10T23:51:36Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-a5ddac889b394ae08a5b507f2a91b5742023-01-10T18:32:18ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462023-01-011010.3389/fchem.2022.10879631087963Generating a conformational landscape of ubiquitin chains at atomistic resolution by back-mapping based samplingSimon Hunkler0Teresa Buhl1Oleksandra Kukharenko2Christine Peter3Department of Chemistry, University of Konstanz, Konstanz, GermanyDepartment of Chemistry, University of Konstanz, Konstanz, GermanyMax Planck Institute for Polymer Research, Mainz, GermanyDepartment of Chemistry, University of Konstanz, Konstanz, GermanyUbiquitin chains are flexible multidomain proteins that have important biological functions in cellular signalling. Computational studies with all-atom molecular dynamics simulations of the conformational spaces of polyubiquitins can be challenging due to the system size and a multitude of long-lived meta-stable states. Coarse graining is an efficient approach to overcome this problem—at the cost of losing high-resolution details. Recently, we proposed the back-mapping based sampling (BMBS) approach that reintroduces atomistic information into a given coarse grained (CG) sampling based on a two-dimensional (2D) projection of the conformational landscape, produces an atomistic ensemble and allows to systematically compare the ensembles at the two levels of resolution. Here, we apply BMBS to K48-linked tri-ubiquitin, showing its applicability to larger systems than those it was originally introduced on and demonstrating that the algorithm scales very well with system size. In an extension of the original BMBS we test three different seeding strategies, i.e. different approaches from where in the CG landscape atomistic trajectories are initiated. Furthermore, we apply a recently introduced conformational clustering algorithm to the back-mapped atomistic ensemble. Thus, we obtain insight into the structural composition of the 2D landscape and illustrate that the dimensionality reduction algorithm separates different conformational characteristics very well into different regions of the map. This cluster analysis allows us to show how atomistic trajectories sample conformational states, move through the projection space and in sum converge to an atomistic conformational landscape that slightly differs from the original CG map, indicating a correction of flaws in the CG template.https://www.frontiersin.org/articles/10.3389/fchem.2022.1087963/fullmolecular dynamics simulationsdimensionality reductionback-mappingcoarse grainingclusteringubiquitin |
| spellingShingle | Simon Hunkler Teresa Buhl Oleksandra Kukharenko Christine Peter Generating a conformational landscape of ubiquitin chains at atomistic resolution by back-mapping based sampling Frontiers in Chemistry molecular dynamics simulations dimensionality reduction back-mapping coarse graining clustering ubiquitin |
| title | Generating a conformational landscape of ubiquitin chains at atomistic resolution by back-mapping based sampling |
| title_full | Generating a conformational landscape of ubiquitin chains at atomistic resolution by back-mapping based sampling |
| title_fullStr | Generating a conformational landscape of ubiquitin chains at atomistic resolution by back-mapping based sampling |
| title_full_unstemmed | Generating a conformational landscape of ubiquitin chains at atomistic resolution by back-mapping based sampling |
| title_short | Generating a conformational landscape of ubiquitin chains at atomistic resolution by back-mapping based sampling |
| title_sort | generating a conformational landscape of ubiquitin chains at atomistic resolution by back mapping based sampling |
| topic | molecular dynamics simulations dimensionality reduction back-mapping coarse graining clustering ubiquitin |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2022.1087963/full |
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