Intrinsically Disordered Proteins - Bringing together Physics, Computation and Biology
Location: CECAM-ETHZ, Wolfgang Pauli Strasse 27, ETH Hönggerberg, Zurich, Switzerland
Organisers
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):
Methodology:
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]
References
Birthe Brandt Kragelund (University of Copenhagen) - Organiser
Kresten Lindorff-Larsen (University of Copenhagen) - Organiser
Switzerland
Benjamin Schuler (University of Zurich) - Organiser
United States
Robert Best (Laboratory of Chemical Physics, NIDDK, National Institutes of Health) - Organiser & speaker