Water at the surface of proteins plays a crucial biological role. The study of hydration is therefore fundamental for achieving a complete description of key factors determining the protein biology. In this framework, Molecular Dynamics simulations have provided precious tools for elucidating the structure and dynamics of waters in the protein hydration shell. We employed Molecular Dynamics to address on the hydration properties of the Prion Protein, whose misfolding and aggregation is associated to Transmissible Spongiform Encephalopathies. The investigations focused on different states along a likely aggregation pathway specifically analyzing native state, misfolded state and amyloid-like state. The presentation will discuss on the influence that water exerts on protein structural stability [1, 2], intermolecular interactions [3], misfolding [4] and self-assembly [5, 6]. References 1. PNAS (2005) 102:7535-7540. 2. FEBS Letters (2006) 580:2488-2494. 3. Biophysical Journal (2006) 90:3052-61. 4. Biophysical Journal (2007) 93:1284-1292. 5. Proteins (2008) 70:863-872. 6. BBRC (2008) 366:800-806.