Universal Implementation of a Residue-Specific Force Field Based on CMAP Potentials and Free Energy Decomposition

The coupling between neighboring backbone ϕ and ψ dihedral angles (torsions) has been well appreciated in protein force field development, as in correction map (CMAP) potentials. However, although preferences of backbone torsions are significantly affected by side-chain conformation, there has been no easy way to optimize this coupling. Herein, we prove that the three-dimensional (3D) free energy hypersurface of joint (ϕ, ψ, χ₁) torsions can be decomposed into three separated 2D surfaces. Thus, each of the 2D torsional surfaces can be efficiently and automatically optimized using a CMAP potential. This strategy is then used to reparameterize an AMBER force field such that the resulting χ₁-dependent backbone conformational preference can agree excellently with the reference protein coil library statistics. In various validation simulations (including the folding of seven peptides/proteins, backbone dynamics of three folded proteins, and two intrinsically disordered peptides), the new RSFF2C (residue-specific force field with CMAP potentials) force field gives similar or better performance compared with RSFF2. This strategy can be used to implement our RSFF force fields into a variety of molecular dynamics packages easily.