Computational Methodologies for Real-Space Structural Refinement of Large Macromolecular Complexes

Annu Rev Biophys. 2016 Jul 5;45:253-78. doi: 10.1146/annurev-biophys-062215-011113. Epub 2016 May 2.


The rise of the computer as a powerful tool for model building and refinement has revolutionized the field of structure determination for large biomolecular systems. Despite the wide availability of robust experimental methods capable of resolving structural details across a range of spatiotemporal resolutions, computational hybrid methods have the unique ability to integrate the diverse data from multimodal techniques such as X-ray crystallography and electron microscopy into consistent, fully atomistic structures. Here, commonly employed strategies for computational real-space structural refinement are reviewed, and their specific applications are illustrated for several large macromolecular complexes: ribosome, virus capsids, chemosensory array, and photosynthetic chromatophore. The increasingly important role of computational methods in large-scale structural refinement, along with current and future challenges, is discussed.

Keywords: cryo-EM; flexible fitting; hybrid methods; integrative modeling; molecular dynamics; simulation.

Publication types

  • Review

MeSH terms

  • Bacterial Chromatophores / chemistry
  • Capsid / chemistry
  • Cryoelectron Microscopy
  • Crystallography, X-Ray
  • Humans
  • Macromolecular Substances / chemistry*
  • Models, Molecular
  • Multiprotein Complexes / chemistry
  • Ribosomes / chemistry


  • Macromolecular Substances
  • Multiprotein Complexes