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Ab initio protein modeling into CryoEM density maps using EM‐Fold
Author(s) -
Lindert Steffen,
Hofmann Tommy,
Wötzel Nils,
Karakaş Mert,
Stewart Phoebe L.,
Meiler Jens
Publication year - 2012
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.22027
Subject(s) - ab initio , fold (higher order function) , chemistry , loop modeling , crystallography , protein structure prediction , monte carlo method , electron density , protein structure , molecular physics , statistical physics , physics , algorithm , topology (electrical circuits) , computer science , mathematics , combinatorics , statistics , electron , biochemistry , organic chemistry , quantum mechanics , programming language
EM‐Fold was used to build models for nine proteins in the maps of GroEL (7.7 Å resolution) and ribosome (6.4 Å resolution) in the ab initio modeling category of the 2010 cryo‐electron microscopy modeling challenge. EM‐Fold assembles predicted secondary structure elements (SSEs) into regions of the density map that were identified to correspond to either α‐helices or β‐strands. The assembly uses a Monte Carlo algorithm where loop closure, density‐SSE length agreement, and strength of connecting density between SSEs are evaluated. Top‐scoring models are refined by translating, rotating, and bending SSEs to yield better agreement with the density map. EM‐Fold produces models that contain backbone atoms within SSEs only. The RMSD values of the models with respect to native range from 2.4 to 3.5 Å for six of the nine proteins. EM‐Fold failed to predict the correct topology in three cases. Subsequently, Rosetta was used to build loops and side chains for the very best scoring models after EM‐Fold refinement. The refinement within Rosetta's force field is driven by a density agreement score that calculates a cross‐correlation between a density map simulated from the model and the experimental density map. All‐atom RMSDs as low as 3.4 Å are achieved in favorable cases. Values above 10.0 Å are observed for two proteins with low overall content of secondary structure and hence particularly complex loop modeling problems. RMSDs over residues in secondary structure elements range from 2.5 to 4.8 Å. © 2012 Wiley Periodicals, Inc. Biopolymers 97: 669–677, 2012.