Localizing frustration in native proteins and protein assemblies

Ferreiro, Diego U.; Hegler, Joseph A.; Komives, Elizabeth A.; Wolynes, Peter G.

doi:10.1073/pnas.0709915104

Cited by 322 publications

(473 citation statements)

References 32 publications

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“…It is now textbook knowledge (Williamson, 2012) that proteins are dynamic and that structural states should be treated as ensembles that fluctuate around energy minima. This behavior is described by the energy landscape theory (Frauenfelder et al 1991), which can be applied to protein dynamics using the principle of minimal frustration (Ferreiro et al 2007(Ferreiro et al , 2014Jenik et al 2012). NMR spectroscopy has developed in parallel with the energy landscape theory, and the two research fields are now converging to provide an unprecedented understanding of protein function.…”

Section: Introductionmentioning

confidence: 99%

Protein dynamics and function from solution state NMR spectroscopy

Kovermann

Rogne

Wolf‐Watz

2016

Quart. Rev. Biophys.

148

122

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Abstract. It is well-established that dynamics are central to protein function; their importance is implicitly acknowledged in the principles of the Monod, Wyman and Changeux model of binding cooperativity, which was originally proposed in 1965. Nowadays the concept of protein dynamics is formulated in terms of the energy landscape theory, which can be used to understand protein folding and conformational changes in proteins. Because protein dynamics are so important, a key to understanding protein function at the molecular level is to design experiments that allow their quantitative analysis. Nuclear magnetic resonance (NMR) spectroscopy is uniquely suited for this purpose because major advances in theory, hardware, and experimental methods have made it possible to characterize protein dynamics at an unprecedented level of detail. Unique features of NMR include the ability to quantify dynamics (i) under equilibrium conditions without external perturbations, (ii) using many probes simultaneously, and (iii) over large time intervals. Here we review NMR techniques for quantifying protein dynamics on fast (ps-ns), slow (μs-ms), and very slow (s-min) time scales. These techniques are discussed with reference to some major discoveries in protein science that have been made possible by NMR spectroscopy.

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Section: Introductionmentioning

confidence: 99%

Protein dynamics and function from solution state NMR spectroscopy

Kovermann

Rogne

Wolf‐Watz

2016

Quart. Rev. Biophys.

148

122

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“…The standard deviation was 6.38 for trans peptide bonds with about 12% and 0.5% of residues deviating more than 108and 208, respectively, from planarity. As not all parts of a crystal structure have the same level of reliability, we examined the electron density of every peptide with x 208 from planar to assess which were reliable; then using the reliable examples, we showed that these highly nonplanar peptides are not just in active sites, but represent a mundane aspect of protein structure that simply reflects the "frustration" [16][17][18] that occurs as proteins fold into their tertiary structures. We (see Fig.…”

Section: Introductionmentioning

confidence: 99%

On the reliability of peptide nonplanarity seen in ultra‐high resolution crystal structures

Brereton

Karplus

2016

Protein Science

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Ultra-high resolution protein crystal structures have been considered as relatively reliable sources for defining details of protein geometry, such as the extent to which the peptide unit deviates from planarity. Chellapa and Rose (Proteins 2015; 83:1687) recently called this into question, reporting that for a dozen representative protein structures determined at 1 Å resolution, the diffraction data could be equally well fit with models restrained to have highly planar peptides, i.e. having a standard deviation of the x torsion angles of only 18 instead of the typically observed value of 68. Here, we document both conceptual and practical shortcomings of that study and show that the more tightly restrained models are demonstrably incorrect and do not fit the diffraction data equally well. We emphasize the importance of inspecting electron density maps when investigating the agreement between a model and its experimental data. Overall, this report reinforces that modern standard refinement protocols have been well-conceived and that ultra-high resolution protein crystal structures, when evaluated carefully and used with an awareness of their levels of coordinate uncertainty, are powerful sources of information for providing reliable information about the details of protein geometry.

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“…An idealised conformational selection mechanism would require that it be more likely for the proteins to dissociate before any transition to the bound conformation could occur. 24 This would have presumably been the case if there were a greater degree of "frustration" 76 between the NCBD-like contacts to ACTR, and the contacts stabilizing protein G.…”

Section: B Binding Transition Pathsmentioning

confidence: 99%

Discriminating binding mechanisms of an intrinsically disordered protein via a multi-state coarse-grained model

Knott

Best

2014

The Journal of Chemical Physics

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Many proteins undergo a conformational transition upon binding to their cognate binding partner, with intrinsically disordered proteins (IDPs) providing an extreme example in which a folding transition occurs. However, it is often not clear whether this occurs via an "induced fit" or "conformational selection" mechanism, or via some intermediate scenario. In the first case, transient encounters with the binding partner favour transitions to the bound structure before the two proteins dissociate, while in the second the bound structure must be selected from a subset of unbound structures which are in the correct state for binding, because transient encounters of the incorrect conformation with the binding partner are most likely to result in dissociation. A particularly interesting situation involves those intrinsically disordered proteins which can bind to different binding partners in different conformations. We have devised a multi-state coarse-grained simulation model which is able to capture the binding of IDPs in alternate conformations, and by applying it to the binding of nuclear coactivator binding domain (NCBD) to either ACTR or IRF-3 we are able to determine the binding mechanism. By all measures, the binding of NCBD to either binding partner appears to occur via an induced fit mechanism. Nonetheless, we also show how a scenario closer to conformational selection could arise by choosing an alternative non-binding structure for NCBD. © 2014 AIP Publishing LLC.

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Localizing frustration in native proteins and protein assemblies

Cited by 322 publications

References 32 publications

Protein dynamics and function from solution state NMR spectroscopy

Protein dynamics and function from solution state NMR spectroscopy

On the reliability of peptide nonplanarity seen in ultra‐high resolution crystal structures

Discriminating binding mechanisms of an intrinsically disordered protein via a multi-state coarse-grained model

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