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

Abstract

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.

High-Resolution Mining of SARS-CoV-2 Main Protease Conformational Space: Supercomputer-Driven Unsupervised Adaptive Sampling

“…Two main research groups, DE Shaw Research (DESRES) and RIKEN Center for Biosystems Dynamics Research, recently released multi microseconds MD simulations of the M pro dimer. 6,7 These MD conformational ensembles both used non-polarizable force fields (n-PFF) such as DES-Amber 10 and AMBER14ff 11 . Although they are of great help for the scientific community, conventional MD (cMD) simulation results are however limited by the daunting complexity of M pro 's conformational space, which requires very large computational ressources.…”

Advances in Molecular Dynamics Simulations and Enhanced Sampling Methods for the Study of Protein Systems

“…This force field assimilated per-residue dihedral angle modifications, based on experimental information curated from PDB structures of protein fragments (coil library), into the extant ff99SBnmr1—force field that was formulated based on the backbone dihedral potential of ff99SB and optimized using NMR chemical shifts of fully solved proteins [ 148 ]. Another recent force field that was developed for protein-protein complexes, and concomitantly achieving optimal description for both folded and disordered regions of a protein, is the DES-Amber force field [ 149 ]. This force field was developed by reparametrizing dihedral angle parameters, similar to ff99SBnmr2, and optimizing non-bonded interactions through ab initio QM calculations and experimental data.…”

Cryo-EM structure of Pol κ−DNA−PCNA holoenzyme and implications for polymerase switching in DNA lesion bypass

“…Residues Met225 and Gln281 are in close proximity and were joint by modelling their positions and that of the two bridging residues Gly226 and Leu280. We used the recently developed DES-Amber force field which aims to correctly describe protein-protein interactions 81 . The setup of the simulation closely followed the procedure described in 82 .…”

“…Briefly, the initial structures were solvated in a dodecahedron box 1 nm away from initial protein atoms. The water model used was TIP4P-D also parametrized in conjunction with the protein force field 81 . Na + and Clions were added to simulate a 100 mM NaCl solution.…”