Accurate conformational ensembles of mixed folded proteins from NMR-guided simulations

Intrinsically disordered, low complexity regions often cooperate with folded domains to mediate a variety of protein-protein interactions. To visualize these mixed folded proteins, experimentally guided molecular dynamics simulations are employed but may struggle to simultaneously capture the properties of disordered and folded domains or to generate accurate inter-domain interactions. Here we use solution NMR combined with coarse-grained (CG) simulations to characterize the open state of a mixed-folded construct of the anti-aggregation chaperone DNAJB6 that contains a folded J-domain and a disordered GF linker. By tuning residue-specific dihedral angle parameters that allow CG-simulations to capture the local secondary structure propensities of the linker in coarse-grained simulations, we obtain accurate interdomain contact maps. In agreement with model-free analysis of NMR relaxation data, the resulting ensembles show that even in the open state the linker experiences motions that resemble those of the closed state driven by hydrophobic residues in GF.