Insights into protein compressibility from molecular dynamics simulations

Isothermal compressibility based on molecular dynamics simulations in a nor mal temperature and pressure (NTP)-Gibbs ensemble is estimated for five sol vated globular proteins (bovine pancreatic trypsin inhibitor, trypsin, ribo nuclease A, HEW lysozyme, and alpha -lactalbumin), as well as bulk water, u sing the TIP3P model. Protein intrinsic isothermal compressibilities were c alculated from molecular total volume fluctuations and averages using the s tatistical definition of compressibility. A new and efficient method was de veloped for calculating protein total molecular volume based on an atomic v an der Waals radius extension algorithm. The calculated isothermal compress ibilities are in good agreement with experimental data (the correlation coe fficient is 0.94). The main source of volume fluctuation is the free volume inside the protein, whereas variations in overlap of atomic van der Waals volume are less of a factor. Proteins with low packing density tend to have high compressibility, but packing density alone cannot explain the differe nces in the compressibility among globular proteins. A simple approach to a ssess the contribution to solution compressibility from hydration waters su ggests small differences between hydration and bulk water compressibility. Estimated bulk water compressibility is in excellent agreement with experim ental data. Two criteria for overcoming finite-size effects in bulk water m olecular dynamics simulation are a simulation time longer than 300 ps and a system size larger than 260 water molecules.