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Facing the phase problem.

Wayne A Hendrickson1

  • 1Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.

Iucrj
|September 5, 2023
PubMed
Summary
This summary is machine-generated.

The phase problem in X-ray crystallography has been overcome through evolving methods like anomalous diffraction and molecular replacement. Advances in artificial intelligence and cryo-electron microscopy (cryo-EM) now offer powerful alternatives for determining atomic structures.

Keywords:
anomalous diffractiondensity modificationdirect methodsisomorphous replacementmolecular replacement

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Area of Science:

  • Structural Biology
  • Biophysics
  • Crystallography

Background:

  • X-ray crystallography determines atomic structures from diffraction patterns, but requires evaluating wave phases.
  • The phase problem is a central challenge in structural determination, impacting both theoretical understanding and practical analysis.
  • Historically, macromolecular crystallography relied on isomorphous replacement, later shifting to anomalous diffraction for de novo structure determination.

Purpose of the Study:

  • To review the historical evolution of methods for solving the phase problem in X-ray crystallography.
  • To discuss how the structural biology community has addressed and overcome the phase problem.
  • To highlight current trends and alternative techniques in atomic structure determination.

Main Methods:

  • Evolution of experimental phasing techniques, including isomorphous replacement, multi-wavelength anomalous diffraction (MAD), and single-wavelength anomalous diffraction (SAD).
  • Development and application of molecular replacement, especially with the growth of protein structure databases.
  • Integration of direct methods for specific substructure analysis and the rise of native SAD.
  • Leveraging artificial intelligence (AI) models, such as AlphaFold, for structure prediction and phasing.

Main Results:

  • Anomalous diffraction became dominant for de novo determination, with MAD and SAD being key experimental phasing methods.
  • Molecular replacement, aided by protein family relationships and databases, became the predominant method for known structures.
  • Direct methods found utility in analyzing selenium substructures within SAD.
  • Native SAD exploiting intrinsic atoms (S, P) is now routine, and AI models like AlphaFold are increasingly obviating experimental phasing.

Conclusions:

  • The structural biology community has successfully developed and refined methods to overcome the phase problem in X-ray crystallography.
  • Current techniques, including AI-driven prediction and cryo-EM, provide powerful alternatives and complementary approaches to traditional crystallography.
  • While crystallography's principles remain relevant, cryo-EM offers a direct solution by bypassing the phase problem for many structural biology applications.