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Ensemble completeness in conformer sampling: the case of small macrocycles

In this study we compare the three algorithms for the generation of conformer ensembles Biovia BEST, Schrödinger Prime macrocycle sampling (PMM) and Conformator (CONF) form the University of Hamburg, with ensembles derived for exhaustive molecular dynamics simulations applied to a dataset of 7 small...

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Autores principales: Seep, Lea, Bonin, Anne, Meier, Katharina, Diedam, Holger, Göller, Andreas H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320181/
https://www.ncbi.nlm.nih.gov/pubmed/34325738
http://dx.doi.org/10.1186/s13321-021-00524-0
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author Seep, Lea
Bonin, Anne
Meier, Katharina
Diedam, Holger
Göller, Andreas H.
author_facet Seep, Lea
Bonin, Anne
Meier, Katharina
Diedam, Holger
Göller, Andreas H.
author_sort Seep, Lea
collection PubMed
description In this study we compare the three algorithms for the generation of conformer ensembles Biovia BEST, Schrödinger Prime macrocycle sampling (PMM) and Conformator (CONF) form the University of Hamburg, with ensembles derived for exhaustive molecular dynamics simulations applied to a dataset of 7 small macrocycles in two charge states and three solvents. Ensemble completeness is a prerequisite to allow for the selection of relevant diverse conformers for many applications in computational chemistry. We apply conformation maps using principal component analysis based on ring torsions. Our major finding critical for all applications of conformer ensembles in any computational study is that maps derived from MD with explicit solvent are significantly distinct between macrocycles, charge states and solvents, whereas the maps for post-optimized conformers using implicit solvent models from all generator algorithms are very similar independent of the solvent. We apply three metrics for the quantification of the relative covered ensemble space, namely cluster overlap, variance statistics, and a novel metric, Mahalanobis distance, showing that post-optimized MD ensembles cover a significantly larger conformational space than the generator ensembles, with the ranking PMM > BEST >> CONF. Furthermore, we find that the distributions of 3D polar surface areas are very similar for all macrocycles independent of charge state and solvent, except for the smaller and more strained compound 7, and that there is also no obvious correlation between 3D PSA and intramolecular hydrogen bond count distributions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13321-021-00524-0.
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spelling pubmed-83201812021-07-30 Ensemble completeness in conformer sampling: the case of small macrocycles Seep, Lea Bonin, Anne Meier, Katharina Diedam, Holger Göller, Andreas H. J Cheminform Research Article In this study we compare the three algorithms for the generation of conformer ensembles Biovia BEST, Schrödinger Prime macrocycle sampling (PMM) and Conformator (CONF) form the University of Hamburg, with ensembles derived for exhaustive molecular dynamics simulations applied to a dataset of 7 small macrocycles in two charge states and three solvents. Ensemble completeness is a prerequisite to allow for the selection of relevant diverse conformers for many applications in computational chemistry. We apply conformation maps using principal component analysis based on ring torsions. Our major finding critical for all applications of conformer ensembles in any computational study is that maps derived from MD with explicit solvent are significantly distinct between macrocycles, charge states and solvents, whereas the maps for post-optimized conformers using implicit solvent models from all generator algorithms are very similar independent of the solvent. We apply three metrics for the quantification of the relative covered ensemble space, namely cluster overlap, variance statistics, and a novel metric, Mahalanobis distance, showing that post-optimized MD ensembles cover a significantly larger conformational space than the generator ensembles, with the ranking PMM > BEST >> CONF. Furthermore, we find that the distributions of 3D polar surface areas are very similar for all macrocycles independent of charge state and solvent, except for the smaller and more strained compound 7, and that there is also no obvious correlation between 3D PSA and intramolecular hydrogen bond count distributions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13321-021-00524-0. Springer International Publishing 2021-07-29 /pmc/articles/PMC8320181/ /pubmed/34325738 http://dx.doi.org/10.1186/s13321-021-00524-0 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Seep, Lea
Bonin, Anne
Meier, Katharina
Diedam, Holger
Göller, Andreas H.
Ensemble completeness in conformer sampling: the case of small macrocycles
title Ensemble completeness in conformer sampling: the case of small macrocycles
title_full Ensemble completeness in conformer sampling: the case of small macrocycles
title_fullStr Ensemble completeness in conformer sampling: the case of small macrocycles
title_full_unstemmed Ensemble completeness in conformer sampling: the case of small macrocycles
title_short Ensemble completeness in conformer sampling: the case of small macrocycles
title_sort ensemble completeness in conformer sampling: the case of small macrocycles
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320181/
https://www.ncbi.nlm.nih.gov/pubmed/34325738
http://dx.doi.org/10.1186/s13321-021-00524-0
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