Development of a Force Field for the Simulation of Single-Chain Proteins and Protein–Protein Complexes

The accuracy of atomistic physics-based force fields for the simulation of biological macromolecules has typically been benchmarked experimentally using biophysical data from simple, often single-chain systems. In the case of proteins, the careful refinement of force field parameters associated with torsion-angle potentials and the use of improved water models have enabled a great deal of progress toward the highly accurate simulation of such monomeric systems in both folded and, more recently, disordered states. In living organisms, however, proteins constantly interact with other macromolecules, such as proteins and nucleic acids, and these interactions are often essential for proper biological function. Here, we show that state-of-the-art force fields tuned to provide an accurate description of both ordered and disordered proteins can be limited in their ability to accurately describe protein–protein complexes. This observation prompted us to perform an extensive reparameterization of one variant of the Amber protein force field. Our objective involved refitting not only the parameters associated with torsion-angle potentials but also the parameters used to model nonbonded interactions, the specification of which is expected to be central to the accurate description of multicomponent systems. The resulting force field, which we call DES-Amber, allows for more accurate simulations of protein–protein complexes, while still providing a state-of-the-art description of both ordered and disordered single-chain proteins. Despite the improvements, calculated protein–protein association free energies still appear to deviate substantially from experiment, a result suggesting that more fundamental changes to the force field, such as the explicit treatment of polarization effects, may simultaneously further improve the modeling of single-chain proteins and protein–protein complexes.