MEM-CALVADOS: A Residue-Level Model for Flexible Proteins at Membrane Interfaces
TL;DR
The model provides a computationally efficient framework for studying conformational ensembles and assembly of proteins at bilayer–water interfaces and is validated against Wimley–White free energies of transfer of hydrophobic peptides and against an experimentally refined conformational ensemble of a flexible membrane receptor.
Abstract
Many membrane proteins contain intrinsically disordered regions (IDRs) that play key biological roles by providing structural plasticity, harboring sites for post-translational modifications, and mediating protein clustering and phase separation. Residue-level molecular models parameterized against experimental data have provided insights into how IDR sequence controls conformational properties and phase behavior in soluble proteins. Here, we extend this modeling framework to membrane-associated IDRs. We adapt a coarse-grained lipid model, iSoLFv2, for four phospholipids and combine it with CALVADOS, a residue-level model for IDRs and multi-domain proteins. Protein–lipid cross-interaction parameters are calibrated to reproduce predicted insertion and orientation of transmembrane proteins with diverse architectures. We validate the resulting model against Wimley–White free energies of transfer of hydrophobic peptides and against an experimentally refined conformational ensemble of a flexible membrane receptor. Finally, we show the applicability of the model to a membrane-associated assembly of signaling proteins. The model provides a computationally efficient framework for studying conformational ensembles and assembly of proteins at bilayer–water interfaces.