Volumetric properties such as isothermal compressibility are important molecular parameters that describe the flexibility and rigidity of protein conformation. They are also closely related to the stability of protein structure and the properties of protein-protein interactions. In this work, a novel numerical method was developed and applied to compute the Voronoi volume of proteins from all-atom molecular dynamics simulations in explicit water. The resulting estimation of isothermal compressibility of lysozyme agrees well with reported experimental data. Since our approach takes the solvation structure of a protein explicitly into account, it can be easily extended to study protein volumetric properties in any solvent other than water. In this work, we explored the effects of high pressure (> 2k bar) and solvation in organic solvent on the volumetric properties of lysozyme and subtilisin by analyzing ~100ns all-atom MD trajectories. The results provide important molecular-level insight in explaining the observed enhanced stability of protein under high pressure and the reduced activity of enzymes in organic solvent. In addition to protein volumetric properties, solvation structures under different conditions are also characterized to provide further molecular insight and the basis for theoretical analysis. Finally, volumetric properties are decomposed into the composing elements at the residue-level using a multiscale coarse-grain framework to characterize the intrinsic flexibility and rigidity of protein conformation.