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

Emre Brookes, Mattia Rocco, Patrice Vachette, Jill Trewhella, F. Meneau

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)910-926
Number of pages17
JournalJournal of Applied Crystallography
Volume56
Issue numberPt 4
DOIs
StatePublished - Aug 1 2023

Keywords

  • AlphaFold
  • SAXS
  • ensemble modelling
  • small-angle X-ray scattering
  • structural flexibility

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