SOP-MULTI: A self-organized polymer based coarse-grained model for multi-domain and intrinsically disordered proteins with conformation ensemble consistent with experimental scattering data

Abstract

AbstractMultidomain proteins with long flexible linkers and full-length intrinsically disordered proteins (IDPs) are best defined as an ensemble of conformations rather than a single structure. Determining high-resolution ensemble structures of such proteins poses various challenges using tools from experimental structural biophysics. Integrative approaches combining available low-resolution ensemble-averaged experimental data andin silicobiomolecular reconstructions are now often used for the purpose. However, an exhaustive Boltzmann weighted conformation sampling for large proteins, especially for ones where both the folded and disordered domains exist in the same polypeptide chain, remains a challenge. In this work, we present a 2-site per amino-acid resolution SOP-MULTI force field for simulating coarse-grained models of multidomain proteins. SOP-MULTI combines two well-established self-organized polymer (SOP) models —: (i) SOP-SC models for folded systems and (ii) SOP-IDP for IDPs. For the SOP-MULTI, we train the cross-interaction terms between the beads belonging to the folded and disordered regions to generate experimentally-consistent conformation ensembles for full-length multi-domain proteins such as hnRNPA1, TDP-43, G3BP1, hGHR-ECD, TIA1, HIV-1 Gag, Poly-Ubiquitin and FUS. When back-mapped to all-atom resolution, SOP-MULTI trajectories faithfully recapitulate the scattering data over the range of the reciprocal space. We also show that individual folded domains preserve native contacts with respect to solved folded structures, and root mean square fluctuations of residues in folded domains match those obtained from all-atom molecular dynamics simulations trajectories of the same folded systems. SOP-MULTI Force Field is made available as a LAMMPS-compatible user package along with setup codes for generating the required files for any full-length protein with folded and disordered regions.