Uncovering Differences in Hydration Free Energies and Structures for Model Compound Mimics of Charged Side Chains of Amino Acids

[Image: see text] Free energies of hydration are of fundamental interest for modeling and understanding conformational and phase equilibria of macromolecular solutes in aqueous phases. Of particular relevance to systems such as intrinsically disordered proteins are the free energies of hydration and hydration structures of model compounds that mimic charged side chains of Arg, Lys, Asp, and Glu. Here, we deploy a Thermodynamic Cycle-based Proton Dissociation (TCPD) approach in conjunction with data from direct measurements to obtain estimates for the free energies of hydration for model compounds that mimic the side chains of Arg(+), Lys(+), Asp(–), and Glu(–). Irrespective of the choice made for the hydration free energy of the proton, the TCPD approach reveals clear trends regarding the free energies of hydration for Arg(+), Lys(+), Asp(–), and Glu(–). These trends include asymmetries between the hydration free energies of acidic (Asp(–) and Glu(–)) and basic (Arg(+) and Lys(+)) residues. Further, the TCPD analysis, which relies on a combination of experimental data, shows that the free energy of hydration of Arg(+) is less favorable than that of Lys(+). We sought a physical explanation for the TCPD-derived trends in free energies of hydration. To this end, we performed temperature-dependent calculations of free energies of hydration and analyzed hydration structures from simulations that use the polarizable Atomic Multipole Optimized Energetics for Biomolecular Applications (AMOEBA) force field and water model. At 298 K, the AMOEBA model generates estimates of free energies of hydration that are consistent with TCPD values with a free energy of hydration for the proton of ca. −259 kcal/mol. Analysis of temperature-dependent simulations leads to a structural explanation for the observed differences in free energies of hydration of ionizable residues and reveals that the heat capacity of hydration is positive for Arg(+) and Lys(+) and negative for Asp(–) and Glu(–).