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AlphaFold-predicted protein structures and small-angle X-ray scattering: insights from an extended examination of selected data in the Small-Angle Scattering Biological Data Bank

By providing predicted protein structures from nearly all known protein sequences, the artificial intelligence program AlphaFold (AF) is having a major impact on structural biology. While a stunning accuracy has been achieved for many folding units, predicted unstructured regions and the arrangement...

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Autores principales: Brookes, Emre, Rocco, Mattia, Vachette, Patrice, Trewhella, Jill
Formato: Online Artículo Texto
Lenguaje:English
Publicado: International Union of Crystallography 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10405597/
https://www.ncbi.nlm.nih.gov/pubmed/37555230
http://dx.doi.org/10.1107/S1600576723005344
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author Brookes, Emre
Rocco, Mattia
Vachette, Patrice
Trewhella, Jill
author_facet Brookes, Emre
Rocco, Mattia
Vachette, Patrice
Trewhella, Jill
author_sort Brookes, Emre
collection PubMed
description By providing predicted protein structures from nearly all known protein sequences, the artificial intelligence program AlphaFold (AF) is having a major impact on structural biology. While a stunning accuracy has been achieved for many folding units, predicted unstructured regions and the arrangement of potentially flexible linkers connecting structured domains present challenges. Focusing on single-chain structures without prosthetic groups, an earlier comparison of features derived from small-angle X-ray scattering (SAXS) data taken from the Small-Angle Scattering Biological Data Bank (SASBDB) is extended to those calculated using the corresponding AF-predicted structures. Selected SASBDB entries were carefully examined to ensure that they represented data from monodisperse protein solutions and had sufficient statistical precision and q resolution for reliable structural evaluation. Three examples were identified where there is clear evidence that the single AF-predicted structure cannot account for the experimental SAXS data. Instead, excellent agreement is found with ensemble models generated by allowing for flexible linkers between high-confidence predicted structured domains. A pool of representative structures was generated using a Monte Carlo method that adjusts backbone dihedral allowed angles along potentially flexible regions. A fast ensemble modelling method was employed that optimizes the fit of pair distance distribution functions [P(r) versus r] and intensity profiles [I(q) versus q] computed from the pool to their experimental counterparts. These results highlight the complementarity between AF prediction, solution SAXS and molecular dynamics/conformational sampling for structural modelling of proteins having both structured and flexible regions.
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spelling pubmed-104055972023-08-08 AlphaFold-predicted protein structures and small-angle X-ray scattering: insights from an extended examination of selected data in the Small-Angle Scattering Biological Data Bank Brookes, Emre Rocco, Mattia Vachette, Patrice Trewhella, Jill J Appl Crystallogr Research Papers By providing predicted protein structures from nearly all known protein sequences, the artificial intelligence program AlphaFold (AF) is having a major impact on structural biology. While a stunning accuracy has been achieved for many folding units, predicted unstructured regions and the arrangement of potentially flexible linkers connecting structured domains present challenges. Focusing on single-chain structures without prosthetic groups, an earlier comparison of features derived from small-angle X-ray scattering (SAXS) data taken from the Small-Angle Scattering Biological Data Bank (SASBDB) is extended to those calculated using the corresponding AF-predicted structures. Selected SASBDB entries were carefully examined to ensure that they represented data from monodisperse protein solutions and had sufficient statistical precision and q resolution for reliable structural evaluation. Three examples were identified where there is clear evidence that the single AF-predicted structure cannot account for the experimental SAXS data. Instead, excellent agreement is found with ensemble models generated by allowing for flexible linkers between high-confidence predicted structured domains. A pool of representative structures was generated using a Monte Carlo method that adjusts backbone dihedral allowed angles along potentially flexible regions. A fast ensemble modelling method was employed that optimizes the fit of pair distance distribution functions [P(r) versus r] and intensity profiles [I(q) versus q] computed from the pool to their experimental counterparts. These results highlight the complementarity between AF prediction, solution SAXS and molecular dynamics/conformational sampling for structural modelling of proteins having both structured and flexible regions. International Union of Crystallography 2023-07-20 /pmc/articles/PMC10405597/ /pubmed/37555230 http://dx.doi.org/10.1107/S1600576723005344 Text en © Emre Brookes et al. 2023 https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.
spellingShingle Research Papers
Brookes, Emre
Rocco, Mattia
Vachette, Patrice
Trewhella, Jill
AlphaFold-predicted protein structures and small-angle X-ray scattering: insights from an extended examination of selected data in the Small-Angle Scattering Biological Data Bank
title AlphaFold-predicted protein structures and small-angle X-ray scattering: insights from an extended examination of selected data in the Small-Angle Scattering Biological Data Bank
title_full AlphaFold-predicted protein structures and small-angle X-ray scattering: insights from an extended examination of selected data in the Small-Angle Scattering Biological Data Bank
title_fullStr AlphaFold-predicted protein structures and small-angle X-ray scattering: insights from an extended examination of selected data in the Small-Angle Scattering Biological Data Bank
title_full_unstemmed AlphaFold-predicted protein structures and small-angle X-ray scattering: insights from an extended examination of selected data in the Small-Angle Scattering Biological Data Bank
title_short AlphaFold-predicted protein structures and small-angle X-ray scattering: insights from an extended examination of selected data in the Small-Angle Scattering Biological Data Bank
title_sort alphafold-predicted protein structures and small-angle x-ray scattering: insights from an extended examination of selected data in the small-angle scattering biological data bank
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10405597/
https://www.ncbi.nlm.nih.gov/pubmed/37555230
http://dx.doi.org/10.1107/S1600576723005344
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