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Abstract
There is increasing interest in intrinsically disordered peptides and proteins (IDPs) due to their abundance and functional importance in eukaryotes, as well as their association with various human disorders ranging from cancer to neurodegenerative diseases. Rather than folding into a single, well-defined three-dimensional structure, an IDP fluctuates between an ensemble of interconverting conformational states, which allows some IDPs to interact with several different binding partners, thereby functioning in proteinprotein interaction networks1. Experimental characterization of conformational ensembles of IDPs is challenging; assistance from computer simulations is often needed, as the number of degrees of freedom of an IDP far exceed the number of available experimental observables2. Recent advances in hardware and software allow molecular simulations to reach relevant timescales for sampling IDP conformations, but a major limiting factor lies in the accuracy of their underlying models, typically empirical force fields (FFs)3. Protein FFs were mostly developed to target folded proteins, and their accuracy in modeling IDPs needs to be scrutinized and improved46.