EM-Fold: De Novo Atomic-Detail Protein Structure Determination from Medium-Resolution Density Maps

Lindert, Steffen; Alexander, Nathan; Wötzel, Nils; Karakaş, Mert; Stewart, Phoebe L.; Meiler, Jens

doi:10.1016/j.str.2012.01.023

Cited by 83 publications

(98 citation statements)

References 48 publications

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“…Our previous results and those from other groups have shown that the topology of major secondary structures may not rely on the detection of all secondary structures. In many cases, the topology of major helices is correctly predicted without the detection of short helices Lindert et al, 2012;Lu et al, 2008). Deriving atomic structures from density maps at medium resolutions will inevitably involve sophisticated modeling of uncertainties.…”

Section: Discussionmentioning

confidence: 99%

“…Given the positions of a helices and b strands in a density map, one can match them with secondary structure sequence segments that can be predicted from the amino acid sequence to derive the overall topology of a protein chain (Al Nasr et al, 2011;Baker et al, 2011;Biswas et al, 2012;Lindert et al, 2012;Lu et al, 2008). Once the topology is determined, backbone and side chains can be constructed and evaluated using energy functions (Al Nasr et al, 2010;Lindert et al, 2012;Sun and He, 2009). Pathwalking derives a Ca trace directly from pseudoatoms extracted from the density map (Baker et al, 2012b).…”

Section: Introductionmentioning

confidence: 99%

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Tracing Beta Strands Using StrandTwister from Cryo-EM Density Maps at Medium Resolutions

2014

Structure

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Major secondary structure elements such as α helices and β sheets can be computationally detected from cryoelectron microscopy (cryo-EM) density maps with medium resolutions of 5-10 Å. However, a critical piece of information for modeling atomic structures is missing, because there are no tools to detect β strands from cryo-EM maps at medium resolutions. We propose a method, StrandTwister, to detect the traces of β strands through the analysis of twist, an intrinsic nature of a β sheet. StrandTwister has been tested using 100 β sheets simulated at 10 Å resolution and 39 β sheets computationally detected from cryo-EM density maps at 4.4-7.4 Å resolutions. Although experimentally derived cryo-EM maps contain errors, StrandTwister's best detections over 39 cases were able to detect 81.87% of the β strands, with an overall 1.66 Å two-way distance between the detected and observed β traces. StrandTwister appears to detect the traces of β strands on major β sheets quite accurately, particularly at the central area of a β sheet.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tracing Beta Strands Using StrandTwister from Cryo-EM Density Maps at Medium Resolutions

2014

Structure

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“…This makes it possible to build the entire model at once by using global optimization techniques. At intermediate to low resolution (4-8 Å ), models can be built by detecting secondary structure elements, which can then be connected by modeling the missing loop segments [45][46][47].…”

Section: De Novo Modeling At Intermediate Resolutionmentioning

confidence: 99%

Hybrid methods for macromolecular structure determination: experiment with expectations

Schröder

2015

Current Opinion in Structural Biology

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“…The de novo modeling combines information from the density map and the amino acid sequence of the protein to derive the topology of secondary structure traces [21,23,[37][38][39]. A topology maps the secondary structure traces from the density map to the amino acid sequence, and therefore determines how the protein chain thread through the traces.…”

Section: Introductionmentioning

confidence: 99%

“…This paper investigates the problem of constructing backbone of a protein when the topology of secondary structures is given. EM-fold uses Rosetta to construct the backbone [20,21]. Pathwalking uses pseudo atoms derived from the density map and a constraint satisfaction solver to place Cα atoms [40].…”

Section: Introductionmentioning

confidence: 99%

Deriving Protein Backbone Using Traces Extracted from Density Maps at Medium Resolutions

Nasr

2015

Bioinformatics Research and Applications

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Abstract. Electron cryomicroscopy is an experimental technique that is capable to produce three dimensional gray-scale images for protein molecules, called density maps. At medium resolution, the atomic details of the molecule cannot be visualized from density maps. However, some features of the molecule can be seen such as the locations of major secondary structures and the skeleton of the molecule. In addition, the order and direction of the detected secondary structure traces can be inferred. We introduce a method to construct the entire model of a protein directly for traces extracted from the density map. The initial results show that this method has good potential. A single model was built for each of the 12 proteins used in the test. The RMSD 100 of the models is slightly improved from our previous method. Keywords:Cryo-EM · Volume image · Skeletonization · Protein modeling · Loop modeling IntroductionElectron cryomicroscopy (cryo-EM) is an emerging technique that produces threedimensional (3D) electron density maps at a wide-range of resolutions [1][2][3][4]. When the resolution of density maps is higher than 4Å, the atomic structure can often be derived [5][6][7][8][9]. At the medium resolutions, such as 5-10Å, the backbone and the characteristic features of amino acids are not resolved. It is still challenging to derive the atomic structure from such a density map. When a component of the protein has atomic structure available, fitting can be performed to derive the atomic structure [10][11][12]. When a homologous model is available, rigid or flexible fitting can be used to derive the atomic structure [13][14][15][16][17][18]. However, it is still challenging to find a suitable template for many proteins. De novo modeling is an alternative method to derive atomic structures without relying on template structures [19][20][21][22][23][24]. It relies on the detection of secondary structure positions and the connection patterns encoded in the skeleton of the density map. A number of computational methods have been developed to detect α-helices from the density maps [25][26][27][28][29][30][31]. Most helices longer than two turns can be detected. Most of the major β-sheets can also be detected using various methods such as SheetTracer, SSEhunter,. By analyzing the twist of β-sheet

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EM-Fold: De Novo Atomic-Detail Protein Structure Determination from Medium-Resolution Density Maps

Cited by 83 publications

References 48 publications

Tracing Beta Strands Using StrandTwister from Cryo-EM Density Maps at Medium Resolutions

Tracing Beta Strands Using StrandTwister from Cryo-EM Density Maps at Medium Resolutions

Hybrid methods for macromolecular structure determination: experiment with expectations

Deriving Protein Backbone Using Traces Extracted from Density Maps at Medium Resolutions

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