Incorporating biochemical information and backbone flexibility in RosettaDock for CAPRI rounds 6–12

Chaudhury, Sidhartha; Sircar, Aroop; Sivasubramanian, Arvind; Berrondo, Monica; Gray, Jeffrey J.

doi:10.1002/prot.21731

Cited by 42 publications

(52 citation statements)

References 46 publications

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“…These methods have been intentionally developed to be versatile and can be used in conjunction with ensembles derived from a wide variety of sources, including NMR data, MD simulations, loop ensembles, and homology modeling. Local docking using RosettaDock is featured in a number of successful CAPRI strategies; 27,28,53,61 given the substantial improvements in performance over the standard RosettaDock algorithm, the new methods are a significant step forward in the state of the art of protein-protein docking towards general flexible docking. Incorporation of backbone conformational plasticity into docking might ultimately allow us to expand the list of "dockable" components beyond high-resolution crystal structures to lower-resolution electron microscopy structures, NMR structures, and homology models, which will be essential to applying predictive docking towards a structural understanding of protein interactions in conjunction with ongoing genomic and proteomic efforts.…”

Section: Resultsmentioning

confidence: 99%

“…This model dictates that the bound conformation of a protein exists in response to the presence of the partner in complex, so the backbone conformational space must be sampled explicitly during docking in response to local energetics of the interface. Explicit backbone flexibility has been modeled primarily using MD, [22][23][24] energy minimization, 23,25 or gradient-based methods in MC minimization, 26,27 but not FFT-based methods. Wang et al have shown impressive results in docking proteins in which a loop undergoes moderate to large conformational changes upon binding using explicit backbone flexibility, but their methods are extremely computationally intensive and require prior knowledge of the flexible regions, limiting their use in blind structure prediction.…”

Section: Introductionmentioning

confidence: 99%

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Conformer Selection and Induced Fit in Flexible Backbone Protein–Protein Docking Using Computational and NMR Ensembles

Chaudhury

Gray

2008

Journal of Molecular Biology

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163

175

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Accommodating backbone flexibility continues to be the most difficult challenge in computational docking of protein-protein complexes. Towards that end, we simulate four distinct biophysical models of protein binding in RosettaDock, a multiscale Monte-Carlo-based algorithm that uses a quasi-kinetic search process to emulate the diffusional encounter of two proteins and to identify low-energy complexes. The four binding models are as follows: (1) key-lock (KL) model, using rigid-backbone docking; (2) conformer selection (CS) model, using a novel ensemble docking algorithm; (3) induced fit (IF) model, using energy-gradient-based backbone minimization; and (4) combined conformer selection/induced fit (CS/IF) model. Backbone flexibility was limited to the smaller partner of the complex, structural ensembles were generated using Rosetta refinement methods, and docking consisted of local perturbations around the complexed conformation using unbound component crystal structures for a set of 21 target complexes. The lowest-energy structure contained >30% of the native residue-residue contacts for 9, 13, 13, and 14 targets for KL, CS, IF, and CS/IF docking, respectively. When applied to 15 targets using nuclear magnetic resonance ensembles of the smaller protein, the lowest-energy structure recovered at least 30% native residue contacts in 3, 8, 4, and 8 targets for KL, CS, IF, and CS/IF docking, respectively. CS/IF docking of the nuclear magnetic resonance ensemble performed equally well or better than KL docking with the unbound crystal structure in 10 of 15 cases. The marked success of CS and CS/IF docking shows that ensemble docking can be a versatile and effective method for accommodating conformational plasticity in docking and serves as a demonstration for the CS theory--that binding-competent conformers exist in the unbound ensemble and can be selected based on their favorable binding energies.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Conformer Selection and Induced Fit in Flexible Backbone Protein–Protein Docking Using Computational and NMR Ensembles

Chaudhury

Gray

2008

Journal of Molecular Biology

Self Cite

163

175

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“…9D). The 2 models were within the top 10 of the most probable structures after running the Rosetta docking server (52). The AUC analysis of the PPCA-NEU1 mixture suggests the existence of only one PPCA-NEU1 heterodimeric complex.…”

Section: Figure 3 Half-life Of Endocytosed Neu1 In Ppcamentioning

confidence: 96%

“…After visualization of the contacts and preliminary analysis of the surface interactions with the computer graphics program COOT (49), several three-dimensional models were suggested based on the optimal packing of the individual monomers. Attempts were undertaken to discriminate between various models using the protein-protein docking servers ClusPro (50), RosettaDock (51,52), and Gramm-X (53, 54), with the knowledge-score algorithms based on surface complementarity, energy optimization, and fast Fourier transformation methodologies, respectively.…”

Section: Structural Modeling Of the Neu1 Oligomer And The Heterodimericmentioning

confidence: 99%

Heterodimerization of the Sialidase NEU1 with the Chaperone Protective Protein/Cathepsin A Prevents Its Premature Oligomerization

Bonten

Campos

Zaĭtsev

et al. 2009

Journal of Biological Chemistry

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Lysosomal neuraminidase-1 (NEU1) forms a multienzyme complex with ␤-galactosidase and protective protein/cathepsin A (PPCA). Because of its association with PPCA, which acts as a molecular chaperone, NEU1 is transported to the lysosomal compartment, catalytically activated, and stabilized. However, the mode(s) of association between these two proteins both en route to the lysosome and in the multienzyme complex has remained elusive. Here, we have analyzed the hydrodynamic properties of PPCA, NEU1, and a complex of the two proteins and identified multiple binding sites on both proteins. One of these sites on NEU1 that is involved in binding to PPCA can also bind to other NEU1 molecules, albeit with lower affinity. Therefore, in the absence of PPCA, as in the lysosomal storage disease galactosialidosis, NEU1 self-associates into chain-like oligomers. Binding of PPCA can reverse self-association of NEU1 by causing the disassembly of NEU1-oligomers and the formation of a PPCA-NEU1 heterodimeric complex. The identification of binding sites between the two proteins allowed us to create innovative structural models of the NEU1 oligomer and the PPCA-NEU1 heterodimeric complex. The proposed mechanism of interaction between NEU1 and its accessory protein PPCA provides a rationale for the secondary deficiency of NEU1 in galactosialidosis.

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“…This poses a challenge due to the 90 M Ube2g2⅐Ub binding affinity, which is weaker than most protein-protein complexes successfully predicted using standard RosettaDock (34). Nevertheless, RosettaDock can take fruitful advantage of cases in which biochemical information (43,44) or multiple/flexible backbone conformations can be incorporated (35,36,44). We have addressed the challenge posed here by low binding affinity by utilizing NMR CSP and PRE measurements to guide sampling toward physically realistic solutions and by allowing for the known flexibility of the ubiquitin C-terminal tail.…”

Section: Ube2g2 Interacts With Both Ubiquitin and Diubiquitin Speciesmentioning

confidence: 99%

Mechanism of Polyubiquitin Chain Recognition by the Human Ubiquitin Conjugating Enzyme Ube2g2

Bocik

Sircar

Gray

et al. 2011

Journal of Biological Chemistry

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Ube2g2 is a human ubiquitin conjugating (E2) enzyme involved in the endoplasmic reticulum-associated degradation pathway, which is responsible for the identification and degradation of unfolded and misfolded proteins in the endoplasmic reticulum compartment. The Ube2g2-specific role is the assembly of Lys-48-linked polyubiquitin chains, which constitutes a signal for proteasomal degradation when attached to a substrate protein. NMR chemical shift perturbation and paramagnetic relaxation enhancement approaches were employed to characterize the binding interaction between Ube2g2 and ubiquitin, Lys-48-linked diubiquitin, and Lys-63-linked diubiquitin. Results demonstrate that ubiquitin binds to Ube2g2 with an affinity of 90 M in two different orientations that are rotated by 180°in models generated by the RosettaDock modeling suite. The binding of Ube2g2 to Lys-48-and Lys-63-linked diubiquitin is primarily driven by interactions with individual ubiquitin subunits, with a clear preference for the subunit containing the free Lys-48 or Lys-63 side chain (i.e. the distal subunit). This preference is particularly striking in the case of Lys-48-linked diubiquitin, which exhibits an ϳ3-fold difference in affinities between the two ubiquitin subunits. This difference can be attributed to the partial steric occlusion of the subunit whose Lys-48 side chain is involved in the isopeptide linkage. As such, these results suggest that Lys-48-linked polyubiquitin chains may be designed to bind certain proteins like Ube2g2 such that the terminal ubiquitin subunit carrying the reactive Lys-48 side chain can be positioned properly for chain elongation regardless of chain length.Proteins to which Lys-48-linked polyubiquitin chains have been attached are destined for degradation by the proteasome (1). The specific polyubiquitylation of protein substrates is accomplished by a cascade of enzymatic steps starting with the ATP-dependent activation of ubiquitin by an E1 protein and culminating in the attachment to substrate of polyubiquitin chains linked together by isopeptide bonds formed between the C terminus of one ubiquitin and the Lys-48 side chain of another ubiquitin (2, 3). Exquisite substrate specificity is achieved by the concerted action of specific pairs of ubiquitin conjugating (E2) and ubiquitin ligase (E3) proteins, of which there are tens and many hundreds found in the cell, respectively.

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Incorporating biochemical information and backbone flexibility in RosettaDock for CAPRI rounds 6–12

Cited by 42 publications

References 46 publications

Conformer Selection and Induced Fit in Flexible Backbone Protein–Protein Docking Using Computational and NMR Ensembles

Conformer Selection and Induced Fit in Flexible Backbone Protein–Protein Docking Using Computational and NMR Ensembles

Heterodimerization of the Sialidase NEU1 with the Chaperone Protective Protein/Cathepsin A Prevents Its Premature Oligomerization

Mechanism of Polyubiquitin Chain Recognition by the Human Ubiquitin Conjugating Enzyme Ube2g2

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