Kinetic hydrate inhibitors (KHIs) are polymers that play a vital role in gas energy production, transport, and storage. A series of polyaspartamides based on L-aspartic acid were designed to serve as potential KHIs. Tuning the fine structures of the polyaspartamides can inhibit the tetrahydrofuran hydrate formation more effectively than classical KHIs, i.e., poly(N-vinylcaprolactam) (PVCap) and poly(N-vinylpyrrolidone) (PVP). When the hydrophobic side chain is longer, the polyaspartamide is more effective. For elucidation of the polymer structure−property relationships in the inhibition of the clathrate hydrate, the molecular-level interactions between the polyaspartamides and tetrahydrofuran hydrate were studied. Dynamics of water surrounding the polymers probed by NMR relaxometry demonstrate that the polyaspartamides can bind tightly with water molecules in the hydrate, resulting in faster transverse relaxation times of the nonfreezable water. This phenomenon can be interpreted by quantum chemical simulations and nonfreezable bound water analysis by calorimetry. The simulations show that the interaction between the polyaspartamides and the clathrate hydrate is featured by the formation of strong hydrogen-bonding, rendering severe distortion and destruction of the clathrate cages. High levels of nonfreezable bound water per polymer repeat unit were found in the amphiphilic polymers. Polyaspartamide could be used as a green resource for prevention of gas hydrate formation in energy production.