Acknowledgements

FINCHES has not emerged out of the ether. It is the result of many years of work by many people. We are grateful to all of them for their contributions. In particular, key in vitro biophysical work characterizing the sequence-dependence of IDR conformational behavior has been instrumental in determinig which types of amino acid interactions are more or less important for IDR-mediated interactions. In parallel, molecular simulations have been essential in building the founditions for how force fields can better capture IDR-associated conformational behavior.

The papers below are far from exaustative, and exclusion of a paper here should not be taken as a slight.

Experimental biophysics

Work to elucidate sequence-ensemble relationships has been conducted by many groups. Below we list a set of papers that have influenced our current understanding of this area.

Crick, S. L., Jayaraman, M., Frieden, C., Wetzel, R. & Pappu, R. V. Fluorescence correlation spectroscopy shows that monomeric polyglutamine molecules form collapsed structures in aqueous solutions. Proc. Natl. Acad. Sci. U.S.A. 103, 16764–16769 (2006).

Mukhopadhyay, S., Krishnan, R., Lemke, E. A., Lindquist, S. & Deniz, A. A. A natively unfolded yeast prion monomer adopts an ensemble of collapsed and rapidly fluctuating structures. Proc. Natl. Acad. Sci. U. S. A. 104, 2649–2654 (2007).

Boze, H., Marlin, T., Durand, D., Pérez, J., Vernhet, A., Canon, F., Sarni-Manchado, P., Cheynier, V. & Cabane, B. Proline-rich salivary proteins have extended conformations. Biophys. J. 99, 656–665 (2010).

Müller-Späth, S., Soranno, A., Hirschfeld, V., Hofmann, H., Rüegger, S., Reymond, L., Nettels, D. & Schuler, B. Charge interactions can dominate the dimensions of intrinsically disordered proteins. Proc. Natl. Acad. Sci. U. S. A. 107, 14609–14614 (2010).

Marsh, J. A. & Forman-Kay, J. D. Sequence determinants of compaction in intrinsically disordered proteins. Biophys. J. 98, 2383–2390 (2010).

Mao, A. H., Crick, S. L., Vitalis, A., Chicoine, C. L. & Pappu, R. V. Net charge per residue modulates conformational ensembles of intrinsically disordered proteins. Proc. Natl. Acad. Sci. U. S. A. 107, 8183–8188 (2010).

Hofmann, H., Soranno, A., Borgia, A., Gast, K., Nettels, D. & Schuler, B. Polymer scaling laws of unfolded and intrinsically disordered proteins quantified with single-molecule spectroscopy. Proc. Natl. Acad. Sci. U. S. A. 109, 16155–16160 (2012).

Das, R. K. & Pappu, R. V. Conformations of intrinsically disordered proteins are influenced by linear sequence distributions of oppositely charged residues. Proc. Natl. Acad. Sci. U. S. A. 110, 13392–13397 (2013).

Holehouse, A. S., Garai, K., Lyle, N., Vitalis, A. & Pappu, R. V. Quantitative assessments of the distinct contributions of polypeptide backbone amides versus side chain groups to chain expansion via chemical denaturation. J. Am. Chem. Soc. 137, 2984–2995 (2015).

Zheng, W., Borgia, A., Buholzer, K., Grishaev, A., Schuler, B. & Best, R. B. Probing the action of chemical denaturant on an intrinsically disordered protein by simulation and experiment. J. Am. Chem. Soc. 138, 11702–11713 (2016).

Borgia, A., Zheng, W., Buholzer, K., Borgia, M. B., Schüler, A., Hofmann, H., Soranno, A., Nettels, D., Gast, K., Grishaev, A., Best, R. B. & Schuler, B. Consistent view of polypeptide chain expansion in chemical denaturants from multiple experimental methods. J. Am. Chem. Soc. 138, 11714–11726 (2016).

Riback, J. A., Bowman, M. A., Zmyslowski, A. M., Knoverek, C. R., Jumper, J. M., Hinshaw, J. R., Kaye, E. B., Freed, K. F., Clark, P. L. & Sosnick, T. R. Innovative scattering analysis shows that hydrophobic disordered proteins are expanded in water. Science 358, 238–241 (2017).

Riback, J. A., Katanski, C. D., Kear-Scott, J. L., Pilipenko, E. V., Rojek, A. E., Sosnick, T. R. & Drummond, D. A. Stress-triggered phase separation is an adaptive, evolutionarily tuned response. Cell 168, 1028-1040.e19 (2017).

Borgia, A., Borgia, M. B., Bugge, K., Kissling, V. M., Heidarsson, P. O., Fernandes, C. B., Sottini, A., Soranno, A., Buholzer, K. J., Nettels, D., Kragelund, B. B., Best, R. B. & Schuler, B. Extreme disorder in an ultrahigh-affinity protein complex. Nature 555, 61–66 (2018).

Sørensen, C. S. & Kjaergaard, M. Effective concentrations enforced by intrinsically disordered linkers are governed by polymer physics. Proc. Natl. Acad. Sci. U. S. A. 116, 23124–23131 (2019).

Martin, E. W., Holehouse, A. S., Peran, I., Farag, M., Incicco, J. J., Bremer, A., Grace, C. R., Soranno, A., Pappu, R. V. & Mittag, T. Valence and patterning of aromatic residues determine the phase behavior of prion-like domains. Science 367, 694–699 (2020).

Computational biophysics

The current implementation of FINCHES is built on top of the CALVADOS and Mpipi coarse-grained force fields. These models have been developed over many years by many people, and themselves are based on many years of careful working developing the physical principles required to capture IDR-associated conformational behavior.

Vitalis, A. & Pappu, R. V. ABSINTH: a new continuum solvation model for simulations of polypeptides in aqueous solutions. J. Comput. Chem. 30, 673–699 (2009).

Robustelli, P., Piana, S. & Shaw, D. E. Developing a molecular dynamics force field for both folded and disordered protein states. Proc. Natl. Acad. Sci. U. S. A. 115, E4758–E4766 (2018).

Wuttke, R., Hofmann, H., Nettels, D., Borgia, M. B., Mittal, J., Best, R. B. & Schuler, B. Temperature-dependent solvation modulates the dimensions of disordered proteins. Proc. Natl. Acad. Sci. U. S. A. 111, 5213–5218 (2014).

Joseph, J. A., Reinhardt, A., Aguirre, A., Chew, P. Y., Russell, K. O., Espinosa, J. R., Garaizar, A. & Collepardo-Guevara, R. Physics-driven coarse-grained model for biomolecular phase separation with near-quantitative accuracy. Nat. Comput. Sci. 1, 732–743 (2021).

Chakravarti, A. & Joseph, J. A. Accurate prediction of thermoresponsive phase behavior of disordered proteins. bioRxivorg 2025.03. 04.641540 (2025). doi:10.1101/2025.03.04.641540

Tesei, G. & Lindorff-Larsen, K. Improved predictions of phase behaviour of intrinsically disordered proteins by tuning the interaction range. Open Res. Eur. 2, 94 (2022).

Tesei, G., Schulze, T. K., Crehuet, R. & Lindorff-Larsen, K. Accurate model of liquid-liquid phase behavior of intrinsically disordered proteins from optimization of single-chain properties. Proc. Natl. Acad. Sci. U. S. A. 118, e2111696118 (2021).