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Refinement of AlphaFold2 models against experimental and hybrid cryo-EM density maps

Recent breakthroughs in deep learning-based protein structure prediction show that it is possible to obtain highly accurate models for a wide range of difficult protein targets for which only the amino acid sequence is known. The availability of accurately predicted models from sequences can potenti...

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Autores principales: Alshammari, Maytha, Wriggers, Willy, Sun, Jiangwen, He, Jing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cambridge University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10361706/
https://www.ncbi.nlm.nih.gov/pubmed/37485023
http://dx.doi.org/10.1017/qrd.2022.13
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author Alshammari, Maytha
Wriggers, Willy
Sun, Jiangwen
He, Jing
author_facet Alshammari, Maytha
Wriggers, Willy
Sun, Jiangwen
He, Jing
author_sort Alshammari, Maytha
collection PubMed
description Recent breakthroughs in deep learning-based protein structure prediction show that it is possible to obtain highly accurate models for a wide range of difficult protein targets for which only the amino acid sequence is known. The availability of accurately predicted models from sequences can potentially revolutionise many modelling approaches in structural biology, including the interpretation of cryo-EM density maps. Although atomic structures can be readily solved from cryo-EM maps of better than 4 Å resolution, it is still challenging to determine accurate models from lower-resolution density maps. Here, we report on the benefits of models predicted by AlphaFold2 (the best-performing structure prediction method at CASP14) on cryo-EM refinement using the Phenix refinement suite for AlphaFold2 models. To study the robustness of model refinement at a lower resolution of interest, we introduced hybrid maps (i.e. experimental cryo-EM maps) filtered to lower resolutions by real-space convolution. The AlphaFold2 models were refined to attain good accuracies above 0.8 TM scores for 9 of the 13 cryo-EM maps. TM scores improved for AlphaFold2 models refined against all 13 cryo-EM maps of better than 4.5 Å resolution, 8 hybrid maps of 6 Å resolution, and 3 hybrid maps of 8 Å resolution. The results show that it is possible (at least with the Phenix protocol) to extend the refinement success below 4.5 Å resolution. We even found isolated cases in which resolution lowering was slightly beneficial for refinement, suggesting that high-resolution cryo-EM maps might sometimes trap AlphaFold2 models in local optima.
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spelling pubmed-103617062023-07-21 Refinement of AlphaFold2 models against experimental and hybrid cryo-EM density maps Alshammari, Maytha Wriggers, Willy Sun, Jiangwen He, Jing QRB Discov Research Article Recent breakthroughs in deep learning-based protein structure prediction show that it is possible to obtain highly accurate models for a wide range of difficult protein targets for which only the amino acid sequence is known. The availability of accurately predicted models from sequences can potentially revolutionise many modelling approaches in structural biology, including the interpretation of cryo-EM density maps. Although atomic structures can be readily solved from cryo-EM maps of better than 4 Å resolution, it is still challenging to determine accurate models from lower-resolution density maps. Here, we report on the benefits of models predicted by AlphaFold2 (the best-performing structure prediction method at CASP14) on cryo-EM refinement using the Phenix refinement suite for AlphaFold2 models. To study the robustness of model refinement at a lower resolution of interest, we introduced hybrid maps (i.e. experimental cryo-EM maps) filtered to lower resolutions by real-space convolution. The AlphaFold2 models were refined to attain good accuracies above 0.8 TM scores for 9 of the 13 cryo-EM maps. TM scores improved for AlphaFold2 models refined against all 13 cryo-EM maps of better than 4.5 Å resolution, 8 hybrid maps of 6 Å resolution, and 3 hybrid maps of 8 Å resolution. The results show that it is possible (at least with the Phenix protocol) to extend the refinement success below 4.5 Å resolution. We even found isolated cases in which resolution lowering was slightly beneficial for refinement, suggesting that high-resolution cryo-EM maps might sometimes trap AlphaFold2 models in local optima. Cambridge University Press 2022-09-20 /pmc/articles/PMC10361706/ /pubmed/37485023 http://dx.doi.org/10.1017/qrd.2022.13 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by-nd/4.0/This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NoDerivatives licence (http://creativecommons.org/licenses/by-nd/4.0), which permits re-use, distribution, and reproduction in any medium, provided that no alterations are made and the original article is properly cited.
spellingShingle Research Article
Alshammari, Maytha
Wriggers, Willy
Sun, Jiangwen
He, Jing
Refinement of AlphaFold2 models against experimental and hybrid cryo-EM density maps
title Refinement of AlphaFold2 models against experimental and hybrid cryo-EM density maps
title_full Refinement of AlphaFold2 models against experimental and hybrid cryo-EM density maps
title_fullStr Refinement of AlphaFold2 models against experimental and hybrid cryo-EM density maps
title_full_unstemmed Refinement of AlphaFold2 models against experimental and hybrid cryo-EM density maps
title_short Refinement of AlphaFold2 models against experimental and hybrid cryo-EM density maps
title_sort refinement of alphafold2 models against experimental and hybrid cryo-em density maps
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10361706/
https://www.ncbi.nlm.nih.gov/pubmed/37485023
http://dx.doi.org/10.1017/qrd.2022.13
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