Modified polyaspartic acid (PASP) scale inhibitors, Tyr-SA-PASP and Trp-SA-PASP, were prepared through grafting copolymerization on PASP with sulfamic/amino acids, and then applied for the inhibition of calcium sulfate from cooling water. Scale inhibition performance evaluation demonstrated Tyr-SA-PASP and Trp-SA-PASP were two cost-effective scale inhibitors for the inhibition of calcium sulfate: Compared to PASP and two commercial scale inhibitors (PAPEMP and JH-907), both modified PASP scale inhibitors exhibited higher inhibition performance, due to coordination between the deprotonation of carboxylic acid and phenolic hydroxyl groups of Tyr-SA-PASP and carboxylic acid groups of Trp-SA-PASP and Ca2+. Scale inhibition mechanism was investigated from microscopic viewpoints: coordination was the intrinsic driving force; Modified PASP scale inhibitors significantly damaged the crystalline structure of calcium sulfate scale, which resulted from coordination between functional groups on modified PASP scale inhibitors and Ca2+; The scale inhibition ability of modified PASP scale inhibitors came from the prevention of the growth of crystal planes ({040}, {041} and {113}). The current study provided a strategy for the design of scale inhibitors from the viewpoint of chemical structures.