Modeling of proteins and their assemblies with the integrative modeling platform

Benjamin Webb, Keren Lasker, Javier Velázquez-Muriel, Dina Schneidman-Duhovny, Riccardo Pellarin, Massimiliano Bonomi, Charles Greenberg, Barak Raveh, Elina Tjioe, Daniel Russel, Andrej Sali

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

27 Scopus citations

Abstract

To understand the workings of the living cell, we need to characterize protein assemblies that constitute the cell (for example, the ribosome, 26S proteasome, and the nuclear pore complex). A reliable high-resolution structural characterization of these assemblies is frequently beyond the reach of current experimental methods, such as X-ray crystallography, NMR spectroscopy, electron microscopy, footprinting, chemical cross-linking, FRET spectroscopy, small angle X-ray scattering, and proteomics. However, the information garnered from different methods can be combined and used to build models of the assembly structures that are consistent with all of the available datasets, and therefore more accurate, precise, and complete. Here, we describe a protocol for this integration, whereby the information is converted to a set of spatial restraints and a variety of optimization procedures can be used to generate models that satisfy the restraints as well as possible. These generated models can then potentially inform about the precision and accuracy of structure determination, the accuracy of the input datasets, and further data generation. We also demonstrate the Integrative Modeling Platform (IMP) software, which provides the necessary computational framework to implement this protocol, and several applications for specific use cases.

Original languageAmerican English
Title of host publicationStructural Genomics
Subtitle of host publicationGeneral Applications
PublisherHumana Press Inc.
Pages277-295
Number of pages19
ISBN (Print)9781627036900
DOIs
StatePublished - 2014
Externally publishedYes

Publication series

NameMethods in Molecular Biology
Volume1091
ISSN (Print)1064-3745

Bibliographical note

Funding Information:
We are grateful to all members of our research group, especially to Frank Alber, Friedrich F?rster, and Bret Peterson who contributed to early versions of IMP, and Marc Marti-Renom, Davide Ba?, Benjamin Schwarz, and Yannick Spill who currently contribute to IMP. We also acknowledge support from National Institutes of Health (R01 GM54762, U54 RR022220, PN2 EY016525, and R01 GM083960) as well as computing hardware support from Ron Conway, Mike Homer, Hewlett-Packard, NetApp, IBM, and Intel.

Keywords

  • Electron microscopy
  • Integrative modeling
  • Protein structure modeling
  • Proteomics of macromolecular assemblies
  • SAXS
  • X-ray crystallography

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