Osmotic Pressure Simulations of Amino Acids and Peptides Highlight Potential Routes to Protein Force Field Parameterization

Recent
molecular dynamics (MD) simulations of proteins have suggested
that common force fields overestimate the strength of amino acid interactions
in aqueous solution. In an attempt to determine the causes of these
effects, we have measured the osmotic coefficients of a number of
amino acids using the AMBER ff99SB-ILDN force field with two popular
water models, and compared the results with available experimental
data. With TIP4P-Ew water, interactions between aliphatic residues
agree well with experiment, but interactions of the polar residues
serine and threonine are found to be excessively attractive. For all
tested amino acids, the osmotic coefficients are lower when the TIP3P
water model is used. Additional simulations performed on charged amino
acids indicate that the osmotic coefficients are strongly dependent
on the parameters assigned to the salt ions, with a reparameterization
of the sodium/carboxylate interaction reported by the Aksimentiev
group significantly improving description of the osmotic coefficient
for glutamate. For five neutral amino acids, we also demonstrate a
decrease in solute–solute attractions using the recently reported
TIP4P-D water model and using the KBFF force field. Finally, we show
that for four two-residue peptides improved agreement with experiment
can be achieved by rederiving the partial charges for each peptide.