<p>Molecular dynamics (MD) simulations have become
increasingly popular in studying the motions and functions of biomolecules. The
accuracy of the simulation, however, is highly determined by the molecular
mechanics (MM) force field (FF), a set of functions with adjustable parameters
to compute the potential energies from atomic positions. However, the overall
quality of the FF, such as our previously published ff99SB and ff14SB, can be
limited by assumptions that were made years ago. In the updated model presented
here (ff19SB), we have significantly improved the backbone profiles for all 20
amino acids. We fit coupled ϕ/ψ parameters using 2D ϕ/ψ conformational scans
for multiple amino acids, using as reference data the entire 2D quantum
mechanics (QM) energy surface. We address the polarization inconsistency during
dihedral parameter fitting by using both QM and MM in solution. Finally, we
examine possible dependency of the backbone fitting on side chain rotamer. To
extensively validate ff19SB parameters, we have performed a total of ~5 milliseconds
MD simulations in explicit solvent. Our results show that after amino-acid
specific training against QM data with solvent polarization, ff19SB not only reproduces
the differences in amino acid specific Protein Data Bank (PDB) Ramachandran
maps better, but also shows significantly improved capability to differentiate
amino acid dependent properties such as helical propensities. We also conclude that
an inherent underestimation of helicity is present in ff14SB, which is
(inexactly) compensated by an increase in helical content driven by the TIP3P
bias toward overly compact structures. In summary, ff19SB, when combined with a
more accurate water model such as OPC, should have better predictive power for
modeling sequence-specific behavior, protein mutations, and also rational
protein design. </p>