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CECAM: From disordered biomolecular complexes to biological coacervates

Recent work has increasingly demonstrated the importance of disorder in biology, exemplified by intrinsically disordered proteins (IDPs). While some IDPs may fold into ordered structures under certain conditions, this workshop will focus on the large class of IDPs or intrinsically disordered regions (IDRs) which perform their functions while remaining largely disordered, as well as their interactions with other biomolecules, in particular nucleic acids. Such proteins include intrinsically disordered linker sequences in large, multidomain proteins [1], disordered molecular chaperones [2], disordered proteins lining the nuclear pore complex [3], disordered protein complexes [4] and those which form biological coacervates by liquid-liquid phase separation [5]. The proposed meeting builds on a series of highly successful and well-attended CECAM meetings on the biophysics of intrinsically disordered proteins organized by us in 2013 (Zürich) and 2015 (Zürich) and in 2017 (Paris). However, this meeting has a more specific focus on disordered molecular complexes and assemblies involving both IDPs and nucleic acids, both in and out of equilibrium.

Understanding the fascinating properties of disordered proteins is a challenging problem, precisely because of their disordered state., which limits the applicable experimental techniques. In addition, for most experiments, the observables are averages over a very broad distribution of configurations, making their interpretation in terms of underlying molecular structure and dynamics a challenging inverse problem. Polymer theory is clearly an important part of the solution, but cannot easily account for the coexistence of both ordered and disordered regions in the protein. Molecular simulation is therefore a key tool for investigating such disordered proteins [6]. Because of the large size of many of the individual proteins and especially for large assemblies and coacervates, the development of coarse-grained models is critical – and likely the most appropriate approach given that the forces driving these interactions are transient and non-specific in nature [7]. Progress will require models with different resolutions, ranging from atomistic with implicit solvent to hyper coarse-grained approaches in which a protein is represented by a single bead, and possibly a multi-scale combination of these.

Both experiments and simulations on disordered proteins are often focused on equilibrium properties (binding thermodynamics, equilibrium flux and rates and phase equilibria). Of course, this is a very useful starting point for understanding the out of equilibrium conditions in biology, but it is clear that inclusion of non-equilibrium effects is essential to understand driving forces and regulation [8,9]. How to include such effects in future theory and simulation models, and the development of experimental systems which are sufficiently complex to capture the phenomenon, but simple enough to be characterized well, will be an important component of the discussions.

[1] C. Sørensen, M. Kjaergaard, Proc Natl Acad Sci USA, 116, 23124-23131 (2019)
[2] R. Schneider, M. Blackledge, M. Jensen, Current Opinion in Structural Biology, 54, 10-18 (2019)
[3] G. Celetti, G. Paci, J. Caria, V. VanDelinder, G. Bachand, E. Lemke, undefined, 219, (2019)
[4] B. Schuler, A. Borgia, M. Borgia, P. Heidarsson, E. Holmstrom, D. Nettels, A. Sottini, Current Opinion in Structural Biology, 60, 66-76 (2020)
[5] J. Choi, A. Holehouse, R. Pappu, Annu. Rev. Biophys., 49, 107-133 (2020)
[6] R. Best, Current Opinion in Structural Biology, 42, 147-154 (2017)
[7] A. Borgia, M. Borgia, K. Bugge, V. Kissling, P. Heidarsson, C. Fernandes, A. Sottini, A. Soranno, K. Buholzer, D. Nettels, B. Kragelund, R. Best, B. Schuler, Nature, 555, 61-66 (2018)
[8] J. Riback, L. Zhu, M. Ferrolino, M. Tolbert, D. Mitrea, D. Sanders, M. Wei, R. Kriwacki, C. Brangwynne, Nature, 581, 209-214 (2020)
[9] S. Ranganathan, E. Shakhnovich, undefined, 9, (2020)