Noncovalent interactions between the guanidinium cation (Gdm(+)) and aromatic amino acids (AAs) in the water molecules have been studied using quantum chemical calculation and molecular dynamics (MD) simulations. Our studies show that there are two different modes of interactions between Gdm(+) and AAs with and without water molecules. It is observed that nonhydrated Gdm(+) interacts with AAs through N-H center dot center dot center dot pi interactions, whereas hydrated clusters of Gdm(+) are stabilized by stacking interactions with the help of the water-mediated hydrogen bond. Thus, different hydration patterns have significant effects on the predominant cation center dot center dot center dot pi interactions in AAs-Gdm(+) complexes. Findings from MD simulation elicit that the interaction pattern of Gdm(+) with AAs varies as Phe < Tyr < Trp. Both the QM and MD calculations show a similar trend in the interaction of AAs with Gdm(+). Moreover, the interaction of AAs with Gdm(+) depends on the spatial orientation of AAs in the protein and the concomitant local structure, that is, the AAs present in the unstructured region of protein such as coils and bends exhibit higher binding for Gdm(+) when compared to the AAs present in the structured region of the protein such as the alpha-helix and the beta-sheet. Our study clearly reveals that H-bonded water molecules and the hydration pattern of Gdm(+) as well as the positional presence of these AAs in the protein structure context play determining roles in the denaturation of protein by the Gdm(+) cation.