Molecular-dynamics simulations were performed on the structures of the water channel aquaporin-1. The results provide an atomistic description of the interactions involved in the water permeation. Two major curvilinear pathways were identified. The simulations confirmed that the water selectivity is due primarily to the size-exclusion effect; i.e., maximally, one water molecule is allowed to pass through the narrow constriction in the aqueous pathway. Most importantly, in contrast to previous proposals, the hydrogen-bonding interactions of water molecules with the polar side chains of Asn-76 and Asn-192 on the strictly conserved Asn-Pro-Ala sequence motifs were found to be essential for maintaining the connectivity of water flow in the narrow constriction region. When Asn-76 and Asn-192 were replaced with near-isosteric hydrophobic residues in the simulation, the aqueous pathways were broken completely. Additionally, the size of the narrow constriction fluctuates significantly during the simulation, which frequently breaks the flow of water and, thus, breaks the single-file water network necessary for proton translocation. Moreover, mutations based on the simulation also have been suggested for further experimental investigation of the water-permeation mechanism of aquaporin-1.