Probing Contributions to the Volume and Isothermal Compressibility of Globular Proteins Using a Fluctuation Solution Theory Analysis of MD Simulations.

Partial molar volumes and compressibilities of four globular native proteins (lysozyme, ribonuclease A, ubiquitin, and α-lactalbumin) were determined from molecular dynamics simulations and the Kirkwood-Buff and Fluctuation Solution theories. Total protein properties were decomposed into individual residue side chain and backbone contributions. By combining the results of constant protonation simulations with those that are largely inaccessible to experiment (e.g., where the motion of protein atoms is greatly reduced or where the net charge on charged side chains is neutralized while retaining bond dipoles), the contributions of volume fluctuations, electrostriction, and changes in hydration to the compressibility were probed. Similarities were found in the properties of the proteins; however, the compressibility change for lysozyme on going from intermediate to low pH was different from the other proteins. The reason for this was revealed through the residue-level decomposition. Solvent exposed carboxylate groups gave a large negative contribution to protein compressibility. At intermediate pH, the overall contribution from acidic residues differed qualitatively for lysozyme as compared to the other three proteins because the lysozyme acidic side chains had more intramolecular polar contacts. Finally, the side chain properties were compared to those obtained from experimental small peptide data modeled using an additive scheme that models unfolded conformation properties.