Structural Assembly of Multidomain Proteins and Protein Complexes Guided by the Overall Rotational Diffusion Tensor

Ryabov, Yaroslav; Fushman, David

doi:10.1021/ja071185d

Cited by 36 publications

(46 citation statements)

References 48 publications

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“…S10. However, we found that one of these intermediate states (labeled I3) similar to the compact structure (PDB 2PE9) which was determined by NMR spectroscopy [34]. The compact X-ray structures might be resulted from the crystal packing forces, therefore are unstable in solution.…”

Section: Resultsmentioning

confidence: 65%

PolyUbiquitin Chain Linkage Topology Selects the Functions from the Underlying Binding Landscape

et al. 2014

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Ubiquitin (Ub) can generate versatile molecular signals and lead to different celluar fates. The functional poly-valence of Ub is believed to be resulted from its ability to form distinct polymerized chains with eight linkage types. To provide a full picture of ubiquitin code, we explore the binding landscape of two free Ub monomers and also the functional landscapes of of all eight linkage types by theoretical modeling. Remarkably, we found that most of the compact structures of covalently connected dimeric Ub chains (diUbs) pre-exist on the binding landscape. These compact functional states were subsequently validated by corresponding linkage models. This leads to the proposal that the folding architecture of Ub monomer has encoded all functional states into its binding landscape, which is further selected by different topologies of polymeric Ub chains. Moreover, our results revealed that covalent linkage leads to symmetry breaking of interfacial interactions. We further propose that topological constraint not only limits the conformational space for effective switching between functional states, but also selects the local interactions for realizing the corresponding biological function. Therefore, the topological constraint provides a way for breaking the binding symmetry and reaching the functional specificity. The simulation results also provide several predictions that qualitatively and quantitatively consistent with experiments. Importantly, the K48 linkage model successfully predicted intermediate states. The resulting multi-state energy landscape was further employed to reconcile the seemingly contradictory experimental data on the conformational equilibrium of K48-diUb. Our results further suggest that hydrophobic interactions are dominant in the functional landscapes of K6-, K11-, K33- and K48 diUbs, while electrostatic interactions play a more important role in the functional landscapes of K27, K29, K63 and linear linkages.

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Section: Resultsmentioning

confidence: 65%

PolyUbiquitin Chain Linkage Topology Selects the Functions from the Underlying Binding Landscape

et al. 2014

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“…This would allow us to account for side chain and backbone flexiblity at the inerface and integrate with all other available experimental data. A recent XPLOR-NIH implementation42 of the diffusion-tensor-guided docking method20 serves as an example. Third, PATIDOCK can be used as the main method for driving molecular docking in a situation where there is a lack of unambiguous intermolecular structural information, like NOEs.…”

Section: Discussionmentioning

confidence: 99%

Structural Assembly of Molecular Complexes Based on Residual Dipolar Couplings

2010

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We present and evaluate a rigid-body molecular docking method, called PATIDOCK, that relies solely on the three-dimensional structure of the individual components and the experimentally derived residual dipolar couplings (RDC) for the complex. We show that, given an accurate ab initio predictor of the alignment tensor from a protein structure, it is possible to accurately assemble a protein-protein complex by utilizing the RDC's sensitivity to molecular shape to guide the docking. The proposed docking method is robust against experimental errors in the RDCs and computationally efficient. We analyze the accuracy and efficiency of this method using experimental or synthetic RDC data for several proteins, as well as synthetic data for a large variety of protein-protein complexes. We also test our method on two protein systems for which the structure of the complex and steric-alignment data are available (Lys48-linked diubiquitin and a complex of ubiquitin and a ubiquitin-associated domain) and analyze the effect of flexible unstructured tails on the outcome of docking. The results demonstrate that it is fundamentally possible to assemble a protein-protein complex based solely on experimental RDC data and the prediction of the alignment tensor from three-dimensional structures. Thus, despite the purely angular nature of residual dipolar couplings, they can be converted into intermolecular distance/ translational constraints. Additionally we show a method for combining RDCs with other experimental data, such as ambiguous constraints from interface mapping, to further improve structure characterization of the protein complexes.

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“…In case of bimolecular systems, we have previously demonstrated that rigid-body alignment and docking of the molecules based on relaxation data alone can provide fairly accurate models for inter-molecular interactions (Ryabov and Fushman, 2007b; Berlin et al, 2011). In ROTIDF 3 we provide a built-in interface, described in the next section, that allows the user to seamlessly switch from simple derivation of the diffusion tensor to immediate quantification of the results (using ELMDOCK(Berlin et al, 2011)) in terms of intermolecular orientation and positioning, without requiring any additional input data or program parameters.…”

Section: Molecular Alignment Docking and Dynamicsmentioning

confidence: 99%

“…(Fushman et al, 1994; Bruschweiler et al, 1995; Mandel et al, 1995; Tjandra et al, 1995; Peng and Wagner, 1995; Tjandra et al, 1997; Fushman et al, 1997; Akke et al, 1997; Fushman and Cowburn, 1998b; Fushman et al, 1999b; Hall and Fushman, 2003; Fushman, 2012). Recently progress has been made on a number of fronts: (i) the improved ability to refine the structures of complexes and quantify molecular motion; (ii) the use of the diffusion tensor as a long-range orientational restraint for the structural characterization of multidomain systems (Fushman et al, 1999b; Ghose et al, 2001; Fushman and Cowburn, 2002; Fushman et al, 2004; Ryabov and Fushman, 2006, 2007a) and for analysis of dynamics of mostly the backbone of proteins (Hall and Fushman, 2003; Fushman et al, 2004; Hall and Fushman, 2006), and rarely for nucleic acid bases and ribose moieties (Akke et al, 1997; Legault et al, 1998; Hoogstraten et al, 2000; Dayie et al, 2002; Boisbouvier et al, 2003; Duchardt and Schwalbe, 2005; Eldho and Dayie, 2007) and (iii) introduction of rotational diffusion tensor as a translational restraint in rigid-body docking of multi-domain proteins and protein-protein complexes (Ryabov and Fushman, 2007b; Ryabov et al, 2010; Berlin et al, 2011). …”

Section: Introductionmentioning

confidence: 99%

Deriving quantitative dynamics information for proteins and RNAs using ROTDIF with a graphical user interface

et al. 2013

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To facilitate rigorous analysis of molecular motions in proteins, DNA, and RNA, we present a new version of ROTDIF, a program for determining the overall rotational diffusion tensor from single-or multiple-field Nuclear Magnetic Resonance (NMR) relaxation data. We introduce four major features that expand the program’s versatility and usability. The first feature is the ability to analyze, separately or together, 13C and/or 15N relaxation data collected at a single or multiple fields. A significant improvement in the accuracy compared to direct analysis of R2/R1 ratios, especially critical for analysis of 13C relaxation data, is achieved by subtracting high-frequency contributions to relaxation rates. The second new feature is an improved method for computing the rotational diffusion tensor in the presence of biased errors, such as large conformational exchange contributions, that significantly enhances the accuracy of the computation. The third new feature is the integration of the domain alignment and docking module for relaxation-based structure determination of multi-domain systems. Finally, to improve accessibility to all the program features, we introduced a graphical user interface (GUI) that simplifies and speeds up the analysis of the data. Written in Java, the new ROTDIF can run on virtually any computer platform. In addition, the new ROTDIF achieves an order of magnitude speedup over the previous version by implementing a more efficient deterministic minimization algorithm. We not only demonstrate the improvement in accuracy and speed of the new algorithm for synthetic and experimental 13C and 15N relaxation data for several proteins and nucleic acids, but also show that careful analysis required especially for characterizing RNA dynamics allowed us to uncover subtle conformational changes in RNA as a function of temperature that were opaque to previous analysis.

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Structural Assembly of Multidomain Proteins and Protein Complexes Guided by the Overall Rotational Diffusion Tensor

Cited by 36 publications

References 48 publications

PolyUbiquitin Chain Linkage Topology Selects the Functions from the Underlying Binding Landscape

PolyUbiquitin Chain Linkage Topology Selects the Functions from the Underlying Binding Landscape

Structural Assembly of Molecular Complexes Based on Residual Dipolar Couplings

Deriving quantitative dynamics information for proteins and RNAs using ROTDIF with a graphical user interface

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