Protein–Protein Docking with Simultaneous Optimization of Rigid-body Displacement and Side-chain Conformations

Gray, Jeffrey J.; Moughon, Stewart; Wang, Chu; Schueler‐Furman, Ora; Kuhlman, Brian; Rohl, Carol A.; Baker, David

doi:10.1016/s0022-2836(03)00670-3

Cited by 1,062 publications

(1,225 citation statements)

References 57 publications

Supporting

Mentioning

1,209

Contrasting

Unclassified

Order By: Relevance

“…Residues 128-130 showed small but potentially significant changes between the two conformations, so we allowed backrub moves of size 2-3 for those residues. In addition to all of those residues, rotamer changes were allowed for residues whose side chains were in the vicinity of the loop using a 5 Å cutoff and by visual inspection (3,7,95 There are several explanations for the difference in the simulations and lack of convergence. In addition to possibly needing more sampling to equilibrate, it may be that the anchor points or other fixed regions of the different starting protein structures bias the loop motion.…”

Section: Test 3: Triosephosphate Isomerase Loop 6 Simulationmentioning

confidence: 99%

Backrub-Like Backbone Simulation Recapitulates Natural Protein Conformational Variability and Improves Mutant Side-Chain Prediction

Smith

Kortemme

2008

Journal of Molecular Biology

297

371

View full text Add to dashboard Cite

SummaryIncorporation of effective backbone sampling into protein simulation and design is an important step in increasing the accuracy of computational protein modeling. Recent analysis of high-resolution crystal structures has suggested a new model, termed backrub, to describe localized, hinge-like alternative backbone and side chain conformations observed in the crystal lattice. The model involves internal backbone rotations about axes between Cα atoms. Based on this observation, we have implemented a backrub-inspired sampling method in the Rosetta structure prediction and design program. We evaluate this model of backbone flexibility using three different tests. First, we show that Rosetta backrub simulations recapitulate the correlation between backbone and side-chain conformations in the high-resolution crystal structures upon which the model was based. As a second test of backrub sampling, we show that backbone flexibility improves the accuracy of predicting point-mutant side chain conformations over fixed backbone rotameric sampling alone. Finally, we show that backrub sampling of triosephosphate isomerase loop 6 can capture the ms/µs oscillation between the open and closed states observed in solution. Our results suggest that backrub sampling captures a sizable fraction of localized conformational changes that occur in natural proteins. Application of this simple model of backbone motions may significantly improve both protein design and atomistic simulations of localized protein flexibility.

show abstract

Section: Test 3: Triosephosphate Isomerase Loop 6 Simulationmentioning

confidence: 99%

Backrub-Like Backbone Simulation Recapitulates Natural Protein Conformational Variability and Improves Mutant Side-Chain Prediction

Smith

Kortemme

2008

Journal of Molecular Biology

297

371

View full text Add to dashboard Cite

show abstract

“…Rigid docking with refinement methods perform rigid docking of the proteins followed by refinement of their side chains [7,9,12,16,26]. By applying side chain refinement, side chain flexibility can be accounted for to improve docking results.…”

Section: Related Workmentioning

confidence: 99%

“…By applying side chain refinement, side chain flexibility can be accounted for to improve docking results. The method of [9] performs optimization of both backbone displacement and side chain conformations based on simulated annealing Monte Carlo. The methods of [7,26] apply biased probability Monte Carlo minimization of the ligand-interacting side chains while [16] uses energy minimization.…”

Section: Related Workmentioning

confidence: 99%

“…Docking is framed as a rigid alignment problem of two rigid objects with complementary shapes. Flexible docking algorithms solve the general protein docking problem termed unbound or predictive docking by prediction of binding of two proteins in their free or unbound states [7,9,12,16,18,20,22,26]. This problem regards one or both proteins as flexible objects to account for significant conformational shape changes which occur during protein interactions.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Knowledge-Guided Docking of WW Domain Proteins and Flexible Ligands

Haiyun

Rashid

et al. 2009

Pattern Recognition in Bioinformatics

View full text Add to dashboard Cite

Abstract. Studies of interactions between protein domains and ligands are important in many aspects such as cellular signaling. We present a knowledge-guided approach for docking protein domains and flexible ligands. The approach is applied to the WW domain, a small protein module mediating signaling complexes which have been implicated in diseases such as muscular dystrophy and Liddle's syndrome. The first stage of the approach employs a substring search for two binding grooves of WW domains and possible binding motifs of peptide ligands based on known features. The second stage aligns the ligand's peptide backbone to the two binding grooves using a quasi-Newton constrained optimization algorithm. The backbone-aligned ligands produced serve as good starting points to the third stage which uses any flexible docking algorithm to perform the docking. The experimental results demonstrate that the backbone alignment method in the second stage performs better than conventional rigid superposition given two binding constraints. It is also shown that using the backbone-aligned ligands as initial configurations improves the flexible docking in the third stage. The presented approach can also be applied to other protein domains that involve binding of flexible ligand to two or more binding sites.

show abstract

“…The possible structures are typically generated by sampling the space of rotations and translations of the docked subunit with respect to the fixed subunit. [9][10][11][12][13][14][15] Alternatively, geometric hashing 16 samples conformations that are consistent with shape complementarity. Scoring is usually based on shape and chemical complementarity.…”

Section: Introductionmentioning

confidence: 99%

Structure determination of symmetric homo‐oligomers by a complete search of symmetry configuration space, using NMR restraints and van der Waals packing

et al. 2006

View full text Add to dashboard Cite

Structural studies of symmetric homo-oligomers provide mechanistic insights into their roles in essential biological processes, including cell signaling and cellular regulation. This paper presents a novel algorithm for homo-oligomeric structure determination, given the subunit structure, that is both complete, in that it evaluates all possible conformations, and data-driven, in that it evaluates conformations separately for consistency with experimental data and for quality of packing. Completeness ensures that the algorithm does not miss the native conformation, and being data-driven enables it to assess the structural precision possible from data alone. Our algorithm performs a branch-and-bound search in the symmetry configuration space, the space of symmetry axis parameters (positions and orientations) defining all possible C n homo-oligomeric complexes for a given subunit structure. It eliminates those symmetry axes inconsistent with intersubunit nuclear Overhauser effect (NOE) distance restraints and then identifies conformations representing any consistent, well-packed structure to within a user-defined similarity level.For the human phospholamban pentamer in dodecylphosphocholine micelles, using the structure of one subunit determined from a subset of the experimental NMR data, our algorithm identifies a diverse set of complex structures consistent with the nine intersubunit NOE restraints. The distribution of determined structures provides an objective characterization of structural uncertainty: backbone RMSD to the previously determined structure ranges from 1.07 to 8.85 Å , and variance in backbone atomic coordinates is an average of 12.32 Å 2 . Incorporating vdW packing reduces structural diversity to a maximum backbone RMSD of 6.24 Å and an average backbone variance of 6.80 Å 2 . By comparing data consistency and packing quality under different assumptions of oligomeric number, our algorithm identifies the pentamer as the most likely oligomeric state of phospholamban, demonstrating that it is possible to determine the oligomeric number directly from NMR data. Additional tests on a number of homo-oligomers, from dimer to heptamer, similarly demonstrate the power of our method to provide unbiased determination and evaluation of homo-oligomeric complex structures.

show abstract

Protein–Protein Docking with Simultaneous Optimization of Rigid-body Displacement and Side-chain Conformations

Cited by 1,062 publications

References 57 publications

Backrub-Like Backbone Simulation Recapitulates Natural Protein Conformational Variability and Improves Mutant Side-Chain Prediction

Backrub-Like Backbone Simulation Recapitulates Natural Protein Conformational Variability and Improves Mutant Side-Chain Prediction

Knowledge-Guided Docking of WW Domain Proteins and Flexible Ligands

Structure determination of symmetric homo‐oligomers by a complete search of symmetry configuration space, using NMR restraints and van der Waals packing

Contact Info

Product

Resources

About