A complete algorithm to resolve ambiguity for intersubunit NOE assignment in structure determination of symmetric homo‐oligomers

Potluri, Shobha; Yan, Anthony K.; Donald, Bruce Randall; Bailey‐Kellogg, Chris

doi:10.1110/ps.062427307

Cited by 17 publications

(35 citation statements)

References 25 publications

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“…The pace of structure determination of membrane proteins has lagged significantly behind soluble globular proteins (White, 2004), in part due to these challenges arising from symmetry. Structure determination of symmetric trimers and higher-order homo-oligomers is hindered by subunit ambiguity (Potluri et al, 2007): even if an NOE between two protons can be assigned as intra-subunit or inter-subunit through X-filtered NOESY (Ikura and Bax, 1992), current experimental techniques are still unable to determine precisely in which subunits the restrained protons lie. Ambiguity can also arise from other sources of experimental uncertainty.…”

Section: Introduction Smentioning

confidence: 99%

“…Ambiguity can also arise from other sources of experimental uncertainty. When overlapping chemical shifts prove difficult to separate, distance restraints can be assigned to multiple atoms, i.e., atom ambiguity (Potluri et al, 2007). Figure 1 illustrates both types of ambiguity.…”

Section: Introduction Smentioning

confidence: 99%

“…For symmetric homo-oligomers of at least three subunits, subunit ambiguity complicates assignment of inter-subunit distance restraints, and hence, calculation of oligomer structures, since naïvely enumerating possible assignment combinations requires exponential time. Potluri et al (2006Potluri et al ( , 2007 employed a branch-and-bound search algorithm which FIG. 1. An inter-subunit distance restraint (yellow dashed lines) for a hypothetical trimeric protein complex can be assigned to multiple subunits (subunit ambiguity), or multiple atoms within a single subunit (atom ambiguity).…”

Section: Introduction Smentioning

confidence: 99%

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A Geometric Arrangement Algorithm for Structure Determination of Symmetric Protein Homo-Oligomers from NOEs and RDCs

Martin

Yan

Bailey‐Kellogg

et al. 2011

Journal of Computational Biology

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Nuclear magnetic resonance (NMR) spectroscopy is a primary tool to perform structural studies of proteins in physiologically-relevant solution conditions. Restraints on distances between pairs of nuclei in the protein, derived from the nuclear Overhauser effect (NOE), provide information about the structure of the protein in its folded state. NMR studies of symmetric protein homo-oligomers present a unique challenge. Using X-filtered NOESY experiments, it is possible to determine whether an NOE restrains a pair of protons across different subunits or within a single subunit, but current experimental techniques are unable to determine in which subunits the restrained protons lie. Consequently, it is difficult to assign NOEs to particular pairs of subunits with certainty, thus hindering the structural analysis of the oligomeric state. Computational approaches are needed to address this subunit ambiguity, but traditional solutions often rely on stochastic search coupled with simulated annealing and simulations of simplified molecular dynamics, which have many tunable parameters that must be chosen carefully and can also fail to report structures consistent with the experimental restraints. In addition, these traditional approaches rarely provide guarantees on running time or solution quality. We reduce the structure determination of homo-oligomers with cyclic symmetry to computing geometric arrangements of unions of annuli in a plane. Our algorithm, disco, runs in expected O(n 2 ) time, where n is the number of distance restraints, potentially assigned ambiguously. disco is guaranteed to report the exact set of oligomer structures consistent with the distance restraints and also with orientational restraints from residual dipolar couplings (RDCs). We demonstrate our method using two symmetric protein complexes: the trimeric E. coli diacylglycerol kinase (DAGK) and a dimeric mutant of the immunoglobulin-binding domain B1 of streptococcal protein G (GB1). In both cases, disco computes oligomer structures with high precision and also finds distance restraints that are either mutually inconsistent or inconsistent with the RDCs. The entire protocol disco has been completely automated in a software package that is freely available and open-source at www.cs.duke.edu/donaldlab/software.php.

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Section: Introduction Smentioning

confidence: 99%

Section: Introduction Smentioning

confidence: 99%

Section: Introduction Smentioning

confidence: 99%

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A Geometric Arrangement Algorithm for Structure Determination of Symmetric Protein Homo-Oligomers from NOEs and RDCs

Martin

Yan

Bailey‐Kellogg

et al. 2011

Journal of Computational Biology

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“…We build upon our earlier work on searching symmetry configuration spaces (Potluri et al, 2006(Potluri et al, , 2007, but this article represents a significant extension in order to support inference and compute error bounds, which account for experimental noise and uncertainty. Our algorithmic approach, hierarchical subdivision with error guarantees, stands in contrast to sampling techniques, such as the replica-exchange MCMC algorithm employed by Nilges and co-workers (Rieping et al, 2005b, Habeck et al, 2005, which may under-sample the high-dimensional and very rugged posterior distribution of a monomer, and does not characterize (or place bounds on) the error in inferred quantities.…”

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confidence: 99%

“…Our original binary algorithm (Potluri et al, 2006) would fail with this set of noisy restraints, since they are inconsistent and the algorithm eliminates a cell if even one NOE is violated. Therefore, we had extended that approach, in the context of NOE assignment, to handle a fixed maximum number of violations (denoted by d) (Potluri et al, 2007). We tested the extended approach on our current datasets.…”

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confidence: 99%

NMR Structural Inference of Symmetric Homo-Oligomers

Chandola

Yan

Potluri

et al. 2011

Journal of Computational Biology

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Symmetric homo-oligomers represent a majority of proteins, and determining their structures helps elucidate important biological processes, including ion transport, signal transduction, and transcriptional regulation. In order to account for the noise and sparsity in the distance restraints used in Nuclear Magnetic Resonance (NMR) structure determination of cyclic (C n ) symmetric homo-oligomers, and the resulting uncertainty in the determined structures, we develop a Bayesian structural inference approach. In contrast to traditional NMR structure determination methods, which identify a small set of low-energy conformations, the inferential approach characterizes the entire posterior distribution of conformations. Unfortunately, traditional stochastic techniques for inference may under-sample the rugged landscape of the posterior, missing important contributions from high-quality individual conformations and not accounting for the possible aggregate effects on inferred quantities from numerous unsampled conformations. However, by exploiting the geometry of symmetric homo-oligomers, we develop an algorithm that provides provable guarantees for the posterior distribution and the inferred mean atomic coordinates. Using experimental restraints for three proteins, we demonstrate that our approach is able to objectively characterize the structural diversity supported by the data. By simulating spurious and missing restraints, we further demonstrate that our approach is robust, degrading smoothly with noise and sparsity.

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