Scholarlink

<p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Experiment-guided AlphaFold3 resolves measurement-consistent protein ensembles

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月29日

查看全文
  • Advaith Maddipatla,
  • Nadav Sellam Bojan,
  • Meital Bojan,
  • Volodymyr Masalitin,
  • Sanketh Vedula,
  • Paul Schanda,
  • Ailie Marx,
  • Alex M. Bronstein

摘要

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.