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Clustering molecular dynamics conformations of the CC’-loop of the PD-1 immuno-checkpoint receptor

Molecular mechanisms within the checkpoint receptor PD-1 are essential for its activation by PD-L1 as well as for blocking such an activation via checkpoint inhibitors. We use molecular dynamics to scrutinize patterns of atomic motion in PD-1 without a ligand. Molecular dynamics is performed for the...

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Autores principales: Schreiner, Wolfgang, Karch, Rudolf, Cibena, Michael, Tomasiak, Lisa, Kenn, Michael, Pfeiler, Georg
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Research Network of Computational and Structural Biotechnology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10432919/
https://www.ncbi.nlm.nih.gov/pubmed/37602229
http://dx.doi.org/10.1016/j.csbj.2023.07.004
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author Schreiner, Wolfgang
Karch, Rudolf
Cibena, Michael
Tomasiak, Lisa
Kenn, Michael
Pfeiler, Georg
author_facet Schreiner, Wolfgang
Karch, Rudolf
Cibena, Michael
Tomasiak, Lisa
Kenn, Michael
Pfeiler, Georg
author_sort Schreiner, Wolfgang
collection PubMed
description Molecular mechanisms within the checkpoint receptor PD-1 are essential for its activation by PD-L1 as well as for blocking such an activation via checkpoint inhibitors. We use molecular dynamics to scrutinize patterns of atomic motion in PD-1 without a ligand. Molecular dynamics is performed for the whole extracellular domain of PD-1, and the analysis focuses on its CC’-loop and some adjacent C(α)-atoms. We extend previous work by applying common nearest neighbor clustering (Cnn) and compare the performance of this method with Daura clustering as well as UMAP dimension reduction and subsequent agglomerative linkage clustering. As compared to Daura clustering, we found Cnn less sensitive to cutoff selection and better able to return representative clusters for sets of different 3D atomic conformations. Interestingly, Cnn yields results quite similar to UMAP plus linkage clustering.
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spelling pubmed-104329192023-08-18 Clustering molecular dynamics conformations of the CC’-loop of the PD-1 immuno-checkpoint receptor Schreiner, Wolfgang Karch, Rudolf Cibena, Michael Tomasiak, Lisa Kenn, Michael Pfeiler, Georg Comput Struct Biotechnol J Research Article Molecular mechanisms within the checkpoint receptor PD-1 are essential for its activation by PD-L1 as well as for blocking such an activation via checkpoint inhibitors. We use molecular dynamics to scrutinize patterns of atomic motion in PD-1 without a ligand. Molecular dynamics is performed for the whole extracellular domain of PD-1, and the analysis focuses on its CC’-loop and some adjacent C(α)-atoms. We extend previous work by applying common nearest neighbor clustering (Cnn) and compare the performance of this method with Daura clustering as well as UMAP dimension reduction and subsequent agglomerative linkage clustering. As compared to Daura clustering, we found Cnn less sensitive to cutoff selection and better able to return representative clusters for sets of different 3D atomic conformations. Interestingly, Cnn yields results quite similar to UMAP plus linkage clustering. Research Network of Computational and Structural Biotechnology 2023-07-13 /pmc/articles/PMC10432919/ /pubmed/37602229 http://dx.doi.org/10.1016/j.csbj.2023.07.004 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Schreiner, Wolfgang
Karch, Rudolf
Cibena, Michael
Tomasiak, Lisa
Kenn, Michael
Pfeiler, Georg
Clustering molecular dynamics conformations of the CC’-loop of the PD-1 immuno-checkpoint receptor
title Clustering molecular dynamics conformations of the CC’-loop of the PD-1 immuno-checkpoint receptor
title_full Clustering molecular dynamics conformations of the CC’-loop of the PD-1 immuno-checkpoint receptor
title_fullStr Clustering molecular dynamics conformations of the CC’-loop of the PD-1 immuno-checkpoint receptor
title_full_unstemmed Clustering molecular dynamics conformations of the CC’-loop of the PD-1 immuno-checkpoint receptor
title_short Clustering molecular dynamics conformations of the CC’-loop of the PD-1 immuno-checkpoint receptor
title_sort clustering molecular dynamics conformations of the cc’-loop of the pd-1 immuno-checkpoint receptor
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10432919/
https://www.ncbi.nlm.nih.gov/pubmed/37602229
http://dx.doi.org/10.1016/j.csbj.2023.07.004
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