Intrinsically Disordered Proteins: Connecting Computation, Physics and Biology
CECAM-ETHZ, Zurich, Switzerland
We are in the midst of a paradigm shift in the way we understand how proteins can perform their functions. Much of the last fifty years of protein research have focused on describing the relationship between protein structure and protein function, with the underlying premise that it is the precise three-dimensional structure of a protein that allows it to perform a specific biological function. While this view has been very successful, it has recently been discovered that the dynamical properties of proteins can play as large and decisive a role as structure in determining and modulating function. The most extreme illustration of this revised view is the discovery of “Intrinsically Disordered Proteins” (IDPs) which, despite the fact that they do not attain a specific three-dimensional structure and instead consist of a broad and fluctuating ensemble of conformations, are involved in a large number of central biological processes. In addition to the extreme level of disorder in IDPs, it is estimated that half of all proteins found in mammals contain long (>30 amino acid residue) sequence stretches that are structurally disordered, and that these stretches of disorder are often essential to function.
Despite progress in the development of methods for characterization of intrinsic disorder by biophysical, biochemical, computational and bioinformatics techniques, there has been a delay in realizing the importance of disorder in the biological studies of proteins and their functions. Further, there has often been a lack of communication between studies within the physical and biological sciences of IDPs. In the physical sciences there has been much focus on a few model systems but less work at studying biological perspectives more broadly. In the biological sciences, there has been a delay in adopting the techniques for e.g. structural modelling that has been developed through e.g. combinations of NMR spectroscopy, computational modelling and theory.
We therefore wish to bring together a number of scientists working in different disciplines on disordered proteins to demonstrate the important synergistic effects that can be attained when combining biophysical, theoretical and biological studies in this area. In contrast to the few other dedicated IDP meetings that have been held so far, which have covered a very broad range of topics, the meeting will be specifically focussed on exploring the link between the structural dynamics of IDPs and their biological functions.
While there was initially much scepticism, it is now generally agreed upon that IDPs are real, that they are abundant, and that they are able to perform special functions in the cell because of their unique properties, providing a strong link to many diseases .
Biophysics: There has been much progress in characterizing the structure and interactions of IDPs through biophysical experiments. Here, NMR spectroscopy has played a particularly central role via its ability to provide atomic level resolution information on highly dynamic systems . Together with single molecule fluorescence  and small-angle scattering techniques  there now exists a battery of experimental methods to provide structural and dynamical information on IDPs. Mostly using experimental methods inspired by the area of protein folding, there has also been important progress in experimental studies of “folding-upon-binding” events , and the connection between such experiments and simulations . Key challenges include determining what is the best combination of experimental techniques that can provide sufficient structural details when integrated with computational modelling.
Simulation: Given the highly dynamical nature of IDPs, and the relative sparsity of experimental data (compared to the large numbers of degrees of freedom), molecular simulations play a central role in structural studies of IDPs. Progress in hardware and simulation techniques has resulted in increased abilities to sample disordered states of proteins [7, 8, 9]. Together with improvements in the force fields used in such simulations [10, 11, 12, 13] it is now possible to model the structural propensities of disordered proteins. Despite the improvements in simulation technology, remaining imperfections necessitate comparison with experiment. This has driven the development of methods in which simulations are directly combined with experiments to characterize structural properties . Conceptually, such methods can be divided into different classes that are based on “generate-and-select”, “biased-sampling” or “iterative-methods”. Important questions include (i) what structural models provide the most accurate descriptions of the short- and long-range structure in IDPs and (ii) what are the best methods for combining progress in sampling methods and structural models (force fields and statistical potentials) with improved abilities to include experimental data in simulations.
Theory: A key observation about disordered proteins is that they can interact with a large number of binding partners. Network theory and systems-wide analysis of expression, regulation and interactions have therefore provided important information about the biology of IDPs . In the context of interactions between folded proteins, the integration of protein motions and interaction networks has recently lead to new insights in to transient binding events . An important challenge for the future is to link more directly the structural features of IDPs with their ability to interact with a broad, but far from random, set of binding partners, as well as what determines the selectivity between the set of protein partners binding to the same site. Recent work has suggested that the ability to interact with multiple binding partners may play a role in enhancing specific over non-specific binding interactions in a complex cellular environment .
Biology: With the realization more broadly that disordered proteins are prevalent and functionally important, studies of their biological role are becoming more common. Most such “biological” studies of disorder, however, do not begin with a desire to study disorder in biology. Instead, they often begin with a biologist studying a particular system only to realize that a functionally important part of the protein is disordered . A particularly common finding in the area has been that disordered regions play central roles in protein regulation and signalling, in particular seen for intracellular domains of membrane receptors involved in cell signalling  and DNA transcription factors . Another promising area of study is how disordered proteins, which might look structurally like either unfolded or partially folded proteins, can escape the cells’ machinery for dealing with misfolded proteins, and how their degradation is regulated. A second challenge presently is to understand how alternative splicing and posttranslational modifications, which are prevalent in IDPs [21, 22], influence binding profiles, conformational ensembles and hence biology. Recently, IDP targeted drugs have emerged holding promises for future alternative therapeutic strategies .
Birthe Brandt Kragelund (University of Copenhagen) - Organiser
Kresten Lindorff-Larsen (University of Copenhagen) - Organiser
Robert Best (Laboratory of Chemical Physics, NIDDK, National Institutes of Health) - Organiser