Table 3.

Comparison of Solvation Free Energies of Glycine and Tri-glycine Using Thermodynamic Integration with Simulations, pDF-Reconstructions, and Benchmark Free Energy Perturbation Calculations^a

Δ G	simulated TI	pDF TI	FEPb
gly1
Δ G vdW	0.39 (0.34)	0.45
Δ G elec	−16.31 (0.12)	−16.25
Δ G total	−15.92 (0.36)	−15.80
gly3, flexible
$\Delta G_{\text{vdW}}^{\text{flex}}$	−0.41 (0.32)	−0.33	−0.03 (0.05)
$\Delta G_{\text{elec}}^{\text{flex}}$		−28.75	−24.01 (0.50)
$\Delta G_{\text{total}}^{\text{flex}}$		−29.08	−24.04 (0.50)
gly3, fixed
$\Delta G_{\text{vdW}}^{\text{fix}}$	−1.29 (0.38)	−1.10	−0.84 (0.04)
$\Delta G_{\text{elec}}^{\text{fix}}$	−25.62 (0.12)	−24.13	−22.08 (0.03)
$\Delta G_{\text{total}}^{\text{fix}}$	−26.91 (0.40)	−25.23	−22.16 (0.05)

^aΔG_vdW is obtained using eq 9. For fixed configurations, ΔG_elec are approximated as half of electrostatic solute–solvent interaction energies using LRT. An average is taken over configurations for flexible solutes. The units are all in kcal/mol.

^bFree energy perturbation results are adapted from ref 65.