SAXS Ensemble Refinement of ESCRT-III CHMP3 Conformational Transitions

Różycki, Bartosz; Kim, Young C.; Hummer, Gerhard

doi:10.1016/j.str.2010.10.006

Cited by 259 publications

(310 citation statements)

References 47 publications

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“…For example, this general recipe describes the approach used in previous analyses of homopeptides (19), the EROS technique for SAXS modeling (18), and the Bayesian Weighting (BW) formalism (24,53). Note that of these three techniques, only BW goes beyond returning a single best-fit ensemble and instead characterizes the posterior distribution via MCMC; below we therefore focus our attention on BW as it is most directly comparable to BELT in scope and purpose.…”

Section: Comparison To Previous Ensemble Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Bayesian Energy Landscape Tilting: Towards Concordant Models of Molecular Ensembles

Beauchamp¹,

Pande²,

Das³

2014

Preprint

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Predicting biological structure has remained challenging for systems such as disordered proteins that take on myriad conformations. Hybrid simulation/experiment strategies have been undermined by difficulties in evaluating errors from computational model inaccuracies and data uncertainties. Building on recent proposals from maximum entropy theory and nonequilibrium thermodynamics, we address these issues through a Bayesian Energy Landscape Tilting (BELT) scheme for computing Bayesian "hyperensembles" over conformational ensembles. BELT uses Markov chain Monte Carlo to directly sample maximum-entropy conformational ensembles consistent with a set of input experimental observables. To test this framework, we apply BELT to model trialanine, starting from disagreeing simulations with the force fields ff96, ff99, ff99sbnmr-ildn, CHARMM27, and OPLS-AA. BELT incorporation of limited chemical shift and 3 J measurements gives convergent values of the peptide's α, β, and P P II conformational populations in all cases. As a test of predictive power, all five BELT hyperensembles recover set-aside measurements not used in the fitting and report accurate errors, even when starting from highly inaccurate simulations. BELT's principled framework thus enables practical predictions for complex biomolecular systems from discordant simulations and sparse data.

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Section: Comparison To Previous Ensemble Methodsmentioning

confidence: 99%

“…Most previous methods have focused on obtaining estimates of a single best-fit conformational ensemble (15,18,19). However, ambiguous experimental data often disallow such a point-estimate of the conformational ensemble.…”

Section: Introductionmentioning

confidence: 99%

Bayesian Energy Landscape Tilting: Towards Concordant Models of Molecular Ensembles

Beauchamp¹,

Pande²,

Das³

2014

Preprint

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“…Monte Carlo simulations of ESCRT-I were carried out using a starting model based on the crystal structures of yeast Vps23 UEV [Protein Data Bank (PDB) ID code 1UZX], yeast Vps28 CTD (PDB ID code 2J9U), the yeast ESCRT-I core (PDB ID code 2P22), a model of the NTH in a helical conformation, and linkers generated in sterically allowed but otherwise arbitrary conformations. The resulting 10,000 conformations were clustered and fit to the experimental IðqÞ curve by using the ensemble refinement of SAXS (EROS) program (30). An acceptable fit could be obtained with a minimum of two conformations, weighted equally ( Fig.…”

Section: Saxs Of Escrt-imentioning

confidence: 99%

Solution structure of the ESCRT-I complex by small-angle X-ray scattering, EPR, and FRET spectroscopy

Bouřa¹,

Różycki

Herrick

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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ESCRT-I is required for the sorting of integral membrane proteins to the lysosome, or vacuole in yeast, for cytokinesis in animal cells, and for the budding of HIV-1 from human macrophages and T lymphocytes. ESCRT-I is a heterotetramer of Vps23, Vps28, Vps37, and Mvb12. The crystal structures of the core complex and the ubiquitin E2 variant and Vps28 C-terminal domains have been determined, but internal flexibility has prevented crystallization of intact ESCRT-I. Here we have characterized the structure of ESCRT-I in solution by simultaneous structural refinement against small-angle X-ray scattering and double electron–electron resonance spectroscopy of spin-labeled complexes. An ensemble of at least six structures, comprising an equally populated mixture of closed and open conformations, was necessary to fit all of the data. This structural ensemble was cross-validated against single-molecule FRET spectroscopy, which suggested the presence of a continuum of open states. ESCRT-I in solution thus appears to consist of an approximately 50% population of one or a few related closed conformations, with the other 50% populating a continuum of open conformations. These conformations provide reference points for the structural pathway by which ESCRT-I induces membrane buds.

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“…In some cases, the method can be applied as a post-analysis treatment on the basis of the initial distribution P 0 (X), as recently done to match small angle X-ray scattering (SAXS) data. 13 But in many applications, the maximum entropy method requires the iterative determination of several coefficients that must be adjusted to satisfy all the experimental constraints. Thus, a question of practical interest is whether the results from restrainedensemble MD simulations can be equivalent to those from the maximum entropy method.…”

Section: Introductionmentioning

confidence: 99%

On the statistical equivalence of restrained-ensemble simulations with the maximum entropy method

Roux

Weare

2013

The Journal of Chemical Physics

187

270

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An issue of general interest in computer simulations is to incorporate information from experiments into a structural model. An important caveat in pursuing this goal is to avoid corrupting the resulting model with spurious and arbitrary biases. While the problem of biasing thermodynamic ensembles can be formulated rigorously using the maximum entropy method introduced by Jaynes, the approach can be cumbersome in practical applications with the need to determine multiple unknown coefficients iteratively. A popular alternative strategy to incorporate the information from experiments is to rely on restrained-ensemble molecular dynamics simulations. However, the fundamental validity of this computational strategy remains in question. Here, it is demonstrated that the statistical distribution produced by restrained-ensemble simulations is formally consistent with the maximum entropy method of Jaynes. This clarifies the underlying conditions under which restrained-ensemble simulations will yield results that are consistent with the maximum entropy method.

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SAXS Ensemble Refinement of ESCRT-III CHMP3 Conformational Transitions

Cited by 259 publications

References 47 publications

Bayesian Energy Landscape Tilting: Towards Concordant Models of Molecular Ensembles

Bayesian Energy Landscape Tilting: Towards Concordant Models of Molecular Ensembles

Solution structure of the ESCRT-I complex by small-angle X-ray scattering, EPR, and FRET spectroscopy

On the statistical equivalence of restrained-ensemble simulations with the maximum entropy method

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