Force Field Benchmark of Amino Acids. 2. Partition Coefficients between Water and Organic Solvents

The partitioning of amino acids between water and apolar environments is of vital importance in protein function and drug delivery. Here we present an extensive benchmark for octanol/water (log Poct), chloroform/water (log Pclf), and cyclohexane/water (log Pchx) partition coefficients of neutral amino acid side chain analogues (SCAs) with Amber families of ff99SB-ILDN, ff03, ff14SB, fb15, and ff15ipq, CHARMM 27, GROMOS 53A6, and OPLS-AA/L force fields. A root-mean-square error (RMSE) of 0.4–1.3 log units from experiment is observed for the tested FFs, of which Amber ff94 lineages of ff99SB-ILDN, ff14SB, and fb15 perform best with an RMSE and mean signed error (MSE) of about 0.5 and 0.2 log units, respectively, a performance comparable with quantum mechanical SMD calculations. This finding retains the possibility of modeling proteins in varied environments with one set of classical molecular mechanical force fields. All the FFs tend to overestimate log P, except for GROMOS 53A6 underestimating log Pclf and log Pchx. These discrepancies are mainly due to the larger overestimated solvation free energies in water (ΔGwat) relative to that in organic solvents (ΔGoct, ΔGclf, and ΔGchx); for GROMOS 53A6, it is due to the underestimated ΔGwat and ΔGoct. The latest water models of “FB” and “OPC” families paired with the recent Amber fb15 do not show an obvious improvement for ΔGwat and log P calculations. The van der Waals interaction between amino acids and cyclohexane is found to be too strong (overestimated) systematically. Scaling protein–water interactions lead to more favorable ΔGwat, thereby lowering log P and resulting in a better performance for Amber ff03ws, while such scaling seems a bit too much for Amber ff99SBws. This, along with our previous work (Zhang et al. J. Chem. Inf. Model. 2018, 58, 1037−1052), may aid in the development and systematic improvements of classical force fields to model proteins in aqueous and nonaqueous phases accurately