Intrinsically Disordered Proteins - Bringing together Physics, Computation and Biology

August 18, 2015 to August 21, 2015
Location : CECAM-ETHZ, Wolfgang Pauli Strasse 27, ETH Hönggerberg, Zurich, Switzerland
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  • Birthe Kragelund (University of Copenhagen, Denmark)
  • Robert Best (Laboratory of Chemical Physics, NIDDK, National Institutes of Health, USA)
  • Kresten Lindorff-Larsen (University of Copenhagen, Denmark)
  • Ben Schuler (University of Zurich, Switzerland)








The purpose of this meeting is to bring together the leading experimentalists (both biophysicists and biologists) together with those doing theory and/or simulation, to determine how the strengths of these different disciplines can best be combined to advance a quantitative understanding of protein disorder, and how disorder is exploited in biology. In particular we believe the following areas/problems could be addressed (the speakers who are expected to be able to contribute most to each area are indicated):

1. Development of predictive simulation models of IDP structure. Clearly molecular simulation can play a key role in characterizing IDPs. However, clear deficiencies in commonly used simulation models have been exposed, for example excessive population of local secondary structure, and radii of gyration much smaller than in experiment. What are the deficiencies of these models in their current format and how can experimental data be used to assess them and to guide their improvement? [Mittal,Bax,Vitalis,Deniz,Piana,Laio]

2. Ensemble structure determination methods. Intrinsically disordered proteins populate a highly diverse ensemble of structures. Different methods have been proposed for characterizing this ensemble, based on different experimental approaches, as well as on molecular simulation. We would like to stimulate discussion on the merits of these different methods and hopefully encourage efforts to combine their strengths. [Jensen,Forman-Kay,Bax,Hummer,Gsponer,Laio]

Outstanding Questions:
1. What are the advantages of intrinsic disorder for protein-protein interactions? Recent work has cast doubt on the conventional “low affinity, high specificity” argument. Do IDPs have an advantage over folded proteins when functioning as ‘hubs’ in protein-protein interaction networks? Or is there an advantage in readily evolving new function without the constraint of being folded? Is there any kinetic advantage for IDP binding? How important are 'supersensitivity effects arising from multiple binding sites? What sorts of models, bioinformatics analysis, and experiments will be needed to answer these questions? [Chan, Chen, Clarke, Teichmann,Gsponer,Takada]

2. Role of IDPs as molecular chaperones. Recent work has revealed that in disordered proteins also play a role as chaperones, preventing misfolding and aggregation of other proteins. What is the mechanism by which these chaperones function and how does it differ from that for folded proteins? [Jakob,Deniz]

3. Effects of sequence and environment on the properties of IDPs. The structure and dynamics of IDPs are clearly determined not only by their sequence, but also by their environment, in particular the environment in the cell. How do effects such as ionic strength, small molecule 'chaperones', macromolecular crowders, temperature and pressure affect the properties of IDPs and how do these effects relate to their function? Can IDPs act as "sensors" of their environment? [Pappu,Mittal,Bax,Goldenberg,Bax,Deniz]

4. How do IDPs avoid aggregation, and when can self-association play a functional role? Many of the peptides which are implicated in disease-associated aggregation into amyloid in fact start out as IDPs. Therefore avoidance of aggregation is clearly a priority for IDPs. Amongst our participants are some of the leaders in experiment and theory related to this problem. [Bax,Gsponer,Clarke,Chan]


[Forman-Kay & Mittag, 2013] From sequence and forces to structure, function and evolution of intrinsically disordered proteins. Forman-Kay JD, Mittag T. Structure. 21:1492-1499. 2013.
[Bardwell & Jakob, 2013] Conditional disorder in chaperone action. Bardwell JCA, Jakob U. Trends Biochem. Sci., 37: 517-525.
[Bernado & Svergun, 2012] Structural analysis of intrinsically disordered proteins by small-angle X-ray scattering. Bernadó P, Svergun DI. Mol Biosyst. 8:151-67. 2012
[Burger et al, 2012] Quasi-anharmonic analysis reveals intermediate States in the nuclear co-activator receptor binding domain ensemble. Burger VM, Ramanathan A, Savol AJ, Stanley CB, Agarwal PK, Chennubhotla CS. Pac Symp Biocomput. 70-81. 2012
[Cumberworth et al., 2014] Promiscuity as a functional trait: intrinsically disordered regions as central players of interactomes. Cumberworth A, Lamour G, Babu M, Gsponer J. Biochem. J. 454:361-369, 2014.
[De Sancho & Best, 2012] Modulation of an IDP binding mechanism and rates by helix propensity and non-native interactions: association of HIF1alpha with CBP. De Sancho D, Best RB. Mol Biosyst. 8:256- 67. 2012
[Dyson, 2011] Expanding the proteome: disordered and alternatively folded proteins. Dyson HJ. Q Rev Biophys. 44:467-518. 2011
[Ferreon et al, 2013] Modulation of allostery by protein intrinsic disorder. Ferreon ACM, Ferreon JC, Wright PE, Deniz AA. Nature. 498:390-394. 2013.
[Ganguly et al, 2013] Electrostatically accelerated encounter and folding for facile recognition of intrinsically disordered proteins. Ganguly D, Zhang W, Chen J. PLoS Comput. Biol., 9:e1003363. 2013.
[Goldenberg & Argyle, 2014] Minimal effects of macromolecular crowding on an intrinsically disordered protein: a small-angle neutron scattering study. Goldenberg DP, Argyle B, Biophys. J. 106:905-914. 2014
[Gsponer et al, 2008] Tight regulation of unstructured proteins: from transcript synthesis to protein degradation. Gsponer J, Futschik ME, Teichmann SA, Babu MM. Science. 322:1365-8. 2008
[Hilser & Thompson, 2011] Structural dynamics, intrinsic disorder, and allostery in nuclear receptors as transcription factors. Hilser VJ, Thompson EB. J Biol Chem. 2011 286:39675-82. 2011
[Jensen et al., 2014] Exploring free-energy landscapes of intrinsically disordered proteins at atomic resolution using NMR spectroscopy. Jensen MR, Zweckstetter M, Huang J-R, Blackledge M, Chem. Rev., 114:6632-6660. 2014.
[Johnson & Hummer, 2011] Nonspecific binding limits the number of proteins in a cell and shapes their interaction networks. Johnson, ME, Hummer G. Proc Natl Acad Sci USA, 108: 603–608. 2011
[Knott & Best, 2012] A Preformed Binding Interface in the Unbound Ensemble of an Intrinsically Disordered Protein: Evidence from Molecular Simulations. Knott M and Best RB. PLoS Comp. Biol., 8: e1002605. 2012.
[Kragelund et al, 2012] Order by disorder in plant signaling. Kragelund, BB, Jensen, MK, Skriver, K. Trends in Plant Sci. 17:625-632, 2012
[Lindorff-Larsen et al, 2012] Structure and dynamics of an unfolded protein examined by molecular dynamics simulation. Lindorff-Larsen K, Trbovic N, Maragakis P, Piana S, Shaw DE. J Am Chem Soc. 134:3787-91. 2012
[Lindorff-Larsen et al, 2012a] Systematic validation of protein force fields against experimental data. Lindorff-Larsen K, Maragakis P, Piana S, Eastwood MP, Dror RO, Shaw DE. PLoS One. 7:e32131. 2012
[Maltsev et al., 2013] Site-specific interaction between alpha-Synuclein and membranes probed by NMR-observed methionine oxidation rates. Maltsev AS, Chen J, Levine RL, Bax A., J. Am. Chem. Soc., 135: 2943-2946. 2013.
[Mao et al., 2013] Describing sequence-ensemble relationships for intrinsically disordered proteins, Mao AH, Lyle N, Pappu RV, 449:307-318. 2013.
[Metallo, 2010] Intrinsically disordered proteins are potential drug targets. Metallo SJ. Curr Opin Chem Biol. 2010 4:481-8. 2010
[Pansca & Fuxreiter, 2012] Interactions via intrinsically disordered regions: what kind of motifs? Pancsa R, Fuxreiter M. IUBMB Life. 64:513-20. 2012
[Piana et al, 2014] Assessing the accuracy of physical models used in protein-folding simulations: quantitative evidence from long molecular dynamics simulations, Piana S, Klepeis JL, Shaw DE. Curr. Opin. Struct. Biol., 24:98-105, 2014.
[Radhakrishnan et al, 2012] Improved Atomistic Monte Carlo Simulations Demonstrate That Poly-l- Proline Adopts Heterogeneous Ensembles of Conformations of Semi-Rigid Segments Interrupted by Kinks. Radhakrishnan A, Vitalis A, Mao AH, Steffen AT, Pappu RV. J Phys Chem B. 116:6862-71 2012
[Rozycki et al., 2011] SAXS ensemble refinement of ESCRT-III CHMP3 conformational transitions. Structure. 19:109-116. 2011
[Romero et al, 2006] Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms. Romero PR, Zaidi S, Fang YY, Uversky VN, Radivojac P, Oldfield CJ, Cortese MS, Sickmeier M, LeGall T, Obradovic Z, Dunker AK. Proc. Natl. Acad. Sci. U.S.A. 103:8390–8395. 2006
[Schneider et al, 2012] Towards a robust description of intrinsic protein disorder using nuclear magnetic resonance spectroscopy. Schneider R, Huang JR, Yao M, Communie G, Ozenne V, Mollica L, Salmon L, Jensen MR, Blackledge M. Mol Biosyst. 8:58-68. 2012
[Sigalov, 2010] Protein intrinsic disorder and oligomericity in cell signaling. Sigalov AB. Mol Biosyst. 6:451-61. 2010
[Shammas et al, 2013] Remarkably fast coupled folding and binding of the intrinsically disordered transactivation domain of cMyb to CBP KIX. Shammas SL, Travis AJ, Clarke J. J. Phys. Chem. B, 117: 13346-13356. 2013.
[Song et al, 2013] Polycation-pi interactions are a driving force for molecular recognition by an intrinsically disordered oncoprotein family. Song J, Ng SC, Tompa P, Lee KAW, Chan HS. PLoS Comput. Biol., 9:e1003239, 2013.
[Vendruscolo, 2007] Determination of conformationally heterogeneous states of proteins. Vendruscolo M. Curr Opin Struct Biol. 2007 17:15-20. 2007
[Wuttke, 2014] Temperature-dependent solvation modulates the dimensions of disordered proteins. Wuttke R, Hofmann H, Nettels D, Borgia MB, Mittal J, Best RB, Schuler B., Proc. Natl. Acad. Sci. U. S. A., 111:5213-5218.