Interface refinement of low- to medium-resolution Cryo-EM complexes using HADDOCK2.4

Tim Neijenhuis; Siri C. van Keulen; Alexandre M.J.J. Bonvin

doi:10.1016/j.str.2022.02.001

Interface refinement of low- to medium-resolution Cryo-EM complexes using HADDOCK2.4

Tim Neijenhuis
, Siri C. van Keulen
, Alexandre M.J.J. Bonvin^*

^*Corresponding author for this work

Utrecht University

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

A wide range of cellular processes requires the formation of multimeric protein complexes. The rise of cryo-electron microscopy (cryo-EM) has enabled the structural characterization of these protein assemblies. The density maps produced can, however, still suffer from limited resolution, impeding the process of resolving structures at atomic resolution. In order to solve this issue, monomers can be fitted into low- to medium-resolution maps. Unfortunately, the models produced frequently contain atomic clashes at the protein-protein interfaces (PPIs), as intermolecular interactions are typically not considered during monomer fitting. Here, we present a refinement approach based on HADDOCK2.4 to remove intermolecular clashes and optimize PPIs. A dataset of 14 cryo-EM complexes was used to test eight protocols. The best-performing protocol, consisting of a semi-flexible simulated annealing refinement with centroid restraints on the monomers, was able to decrease intermolecular atomic clashes by 98% without significantly deteriorating the quality of the cryo-EM density fit.

Original language	English
Pages (from-to)	476-484.e3
Number of pages	13
Journal	Structure
Volume	30
Issue number	4
DOIs	https://doi.org/10.1016/j.str.2022.02.001
Publication status	Published - 7 Apr 2022

Bibliographical note

Funding Information:
This work was performed with the financial support of the Dutch Foundation for Scientific Research (NWO) (PPS Technology Area grant 741.018.201 ) and the European Union Horizon 2020 project BioExcel ( 823830 ).

Publisher Copyright:
© 2022 The Author(s)

Funding

This work was performed with the financial support of the Dutch Foundation for Scientific Research (NWO) (PPS Technology Area grant 741.018.201 ) and the European Union Horizon 2020 project BioExcel ( 823830 ).

Keywords

atomic clashes
electron density map
HADDOCK
interface quality
protein-protein interfaces
refinement

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PIIS0969212622000375Final published version, 3.48 MBLicence: CC BY

Cite this

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title = "Interface refinement of low- to medium-resolution Cryo-EM complexes using HADDOCK2.4",

abstract = "A wide range of cellular processes requires the formation of multimeric protein complexes. The rise of cryo-electron microscopy (cryo-EM) has enabled the structural characterization of these protein assemblies. The density maps produced can, however, still suffer from limited resolution, impeding the process of resolving structures at atomic resolution. In order to solve this issue, monomers can be fitted into low- to medium-resolution maps. Unfortunately, the models produced frequently contain atomic clashes at the protein-protein interfaces (PPIs), as intermolecular interactions are typically not considered during monomer fitting. Here, we present a refinement approach based on HADDOCK2.4 to remove intermolecular clashes and optimize PPIs. A dataset of 14 cryo-EM complexes was used to test eight protocols. The best-performing protocol, consisting of a semi-flexible simulated annealing refinement with centroid restraints on the monomers, was able to decrease intermolecular atomic clashes by 98\% without significantly deteriorating the quality of the cryo-EM density fit.",

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note = "Funding Information: This work was performed with the financial support of the Dutch Foundation for Scientific Research (NWO) (PPS Technology Area grant 741.018.201 ) and the European Union Horizon 2020 project BioExcel ( 823830 ). Publisher Copyright: {\textcopyright} 2022 The Author(s)",

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AU - van Keulen, Siri C.

AU - Bonvin, Alexandre M.J.J.

N1 - Funding Information: This work was performed with the financial support of the Dutch Foundation for Scientific Research (NWO) (PPS Technology Area grant 741.018.201 ) and the European Union Horizon 2020 project BioExcel ( 823830 ). Publisher Copyright: © 2022 The Author(s)

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N2 - A wide range of cellular processes requires the formation of multimeric protein complexes. The rise of cryo-electron microscopy (cryo-EM) has enabled the structural characterization of these protein assemblies. The density maps produced can, however, still suffer from limited resolution, impeding the process of resolving structures at atomic resolution. In order to solve this issue, monomers can be fitted into low- to medium-resolution maps. Unfortunately, the models produced frequently contain atomic clashes at the protein-protein interfaces (PPIs), as intermolecular interactions are typically not considered during monomer fitting. Here, we present a refinement approach based on HADDOCK2.4 to remove intermolecular clashes and optimize PPIs. A dataset of 14 cryo-EM complexes was used to test eight protocols. The best-performing protocol, consisting of a semi-flexible simulated annealing refinement with centroid restraints on the monomers, was able to decrease intermolecular atomic clashes by 98% without significantly deteriorating the quality of the cryo-EM density fit.

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KW - protein-protein interfaces

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Interface refinement of low- to medium-resolution Cryo-EM complexes using HADDOCK2.4

Abstract

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Keywords

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