Significantly Improved Protein Folding Thermodynamics Using a Dispersion-Corrected Water Model and a New Residue-Specific Force Field

An accurate potential
energy model is crucial for biomolecular
simulations. Despite many recent improvements of classical protein
force fields, there are remaining key issues: much weaker temperature
dependence of folding/unfolding equilibrium and overly collapsed unfolded
or disordered states. For the latter problem, a new water model (TIP4P-D)
has been proposed to correct the significantly underestimated water
dispersion interactions. Here, using TIP4P-D, we reveal problems in
current force fields through failures in folding model systems (a
polyalanine peptide, Trp-cage, and the GB1 hairpin). By using residue-specific
parameters to achieve better match between amino acid sequences and
native structures and adding a small H-bond correction to partially
compensate the missing many-body effects in α-helix formation,
the new RSFF2+ force field with the TIP4P-D water model can excellently
reproduce experimental melting curves of both α-helical and
β-hairpin systems. The RSFF2+/TIP4P-D method also gives less
collapsed unfolded structures and describes well folded proteins simultaneously.