---
OA_place: publisher
OA_type: hybrid
PlanS_conform: '1'
_id: '22268'
abstract:
- lang: eng
  text: AlphaFold3 predicts highly accurate protein structures from sequence but tends
    to collapse to a single dominant conformation, even when the underlying structure
    is inherently heterogeneous. Moreover, its predictions are oblivious to experimental
    conditions that can alter local sequence conformation. In this work, we show that
    AlphaFold3 can be guided to match data obtained by nuclear magnetic resonance
    (NMR) spectroscopy, X-ray crystallography and cryogenic electron microscopy (cryo-EM)
    experiments and combinations thereof. Our approach can also incorporate data that
    explicitly report on dynamics, such as site-resolved order parameters. We demonstrate
    that this methodology generates compact structural ensembles whose ensemble-averaged
    observables agree with experiment, with fewer distance restraint violations than
    traditionally resolved NMR structures and with unmodeled alternate conformations
    uncovered in electron density. This methodology paves the way for experimentally
    aware predictive models that generate structural ensembles consistent with the
    measurements, potentially over multiple modalities, and that can be further refined
    toward thermodynamically grounded ensembles by incorporating energetics.
acknowledgement: A. Marx acknowledges the financial support of the Helmsley Fellowships
  Program for Sustainability and Health. A.M.B. and P.S. are supported by the Institute
  of Science and Technology Austria Internal Project Call grant Generative Protein
  NMR. S.V. was supported in part by funding from the Eric and Wendy Schmidt Center
  at the Broad Institute of MIT and Harvard. Open access funding provided by Institute
  of Science and Technology (IST Austria).
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Sai A
  full_name: Maddipatla, Sai A
  id: e957f5e5-91c9-11f0-a95f-e090f66ecb4d
  last_name: Maddipatla
- first_name: Nadav E
  full_name: Sellam, Nadav E
  id: ef280fe0-91c9-11f0-a95f-8dea3f5bc513
  last_name: Sellam
- first_name: Meital I
  full_name: Bojan, Meital I
  id: 11d88cf5-91ca-11f0-a95f-edf9f08f47b7
  last_name: Bojan
- first_name: Vova
  full_name: Masalitin, Vova
  id: ff7958eb-91c9-11f0-a95f-f3bf65828cf6
  last_name: Masalitin
- first_name: Sanketh
  full_name: Vedula, Sanketh
  last_name: Vedula
- first_name: Paul
  full_name: Schanda, Paul
  id: 7B541462-FAF6-11E9-A490-E8DFE5697425
  last_name: Schanda
  orcid: 0000-0002-9350-7606
- first_name: Ailie
  full_name: Marx, Ailie
  last_name: Marx
- first_name: Alexander
  full_name: Bronstein, Alexander
  id: 58f3726e-7cba-11ef-ad8b-e6e8cb3904e6
  last_name: Bronstein
  orcid: 0000-0001-9699-8730
citation:
  ama: Maddipatla SA, Sellam NE, Bojan MI, et al. Experiment-guided AlphaFold3 resolves
    measurement-consistent protein ensembles. <i>Nature Biotechnology</i>. 2026. doi:<a
    href="https://doi.org/10.1038/s41587-026-03166-5">10.1038/s41587-026-03166-5</a>
  apa: Maddipatla, S. A., Sellam, N. E., Bojan, M. I., Masalitin, V., Vedula, S.,
    Schanda, P., … Bronstein, A. M. (2026). Experiment-guided AlphaFold3 resolves
    measurement-consistent protein ensembles. <i>Nature Biotechnology</i>. Springer
    Nature. <a href="https://doi.org/10.1038/s41587-026-03166-5">https://doi.org/10.1038/s41587-026-03166-5</a>
  chicago: Maddipatla, Sai A, Nadav E Sellam, Meital I Bojan, Vova Masalitin, Sanketh
    Vedula, Paul Schanda, Ailie Marx, and Alex M. Bronstein. “Experiment-Guided AlphaFold3
    Resolves Measurement-Consistent Protein Ensembles.” <i>Nature Biotechnology</i>.
    Springer Nature, 2026. <a href="https://doi.org/10.1038/s41587-026-03166-5">https://doi.org/10.1038/s41587-026-03166-5</a>.
  ieee: S. A. Maddipatla <i>et al.</i>, “Experiment-guided AlphaFold3 resolves measurement-consistent
    protein ensembles,” <i>Nature Biotechnology</i>. Springer Nature, 2026.
  ista: Maddipatla SA, Sellam NE, Bojan MI, Masalitin V, Vedula S, Schanda P, Marx
    A, Bronstein AM. 2026. Experiment-guided AlphaFold3 resolves measurement-consistent
    protein ensembles. Nature Biotechnology.
  mla: Maddipatla, Sai A., et al. “Experiment-Guided AlphaFold3 Resolves Measurement-Consistent
    Protein Ensembles.” <i>Nature Biotechnology</i>, Springer Nature, 2026, doi:<a
    href="https://doi.org/10.1038/s41587-026-03166-5">10.1038/s41587-026-03166-5</a>.
  short: S.A. Maddipatla, N.E. Sellam, M.I. Bojan, V. Masalitin, S. Vedula, P. Schanda,
    A. Marx, A.M. Bronstein, Nature Biotechnology (2026).
corr_author: '1'
das_tickbox: '1'
dataavailabilitystatement: All structures and metrics reported in this paper are openly
  available on Harvard Dataverse - https://doi.org/10.7910/DVN/PLYUHN. All code is
  openly available on GitHub (https://github.com/sai-advaith/guided_alphafold); the
  version used for this paper (version 0.9.1) is permanently archived on Zenodo https://doi.org/10.5281/zenodo.17307005
date_created: 2026-07-12T22:02:19Z
date_published: 2026-06-29T00:00:00Z
date_updated: 2026-07-13T09:34:36Z
day: '29'
ddc:
- '570'
department:
- _id: PaSc
- _id: AlBr
- _id: GradSch
doi: 10.1038/s41587-026-03166-5
external_id:
  pmid:
  - '42374114'
has_accepted_license: '1'
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: https://doi.org/10.1038/s41587-026-03166-5
month: '06'
oa: 1
oa_version: Published Version
pmid: 1
publication: Nature Biotechnology
publication_identifier:
  eissn:
  - 1546-1696
  issn:
  - 1087-0156
publication_status: epub_ahead
publisher: Springer Nature
quality_controlled: '1'
researchdata_availability: yes
scopus_import: '1'
status: public
supplementarymaterial: yes
title: Experiment-guided AlphaFold3 resolves measurement-consistent protein ensembles
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
year: '2026'
...