DNA computing, the combination of computer science and molecular biology, is a burgeoning research field that holds promise for many applications. The accuracy of DNA computing is determined by reliable DNA sequences, the quality of which affects the accuracy of hybridization reactions. Evaluating the sequences obtained from the previous combination constraints in NUPACK for simulation experiments, we find that the concentration of the sequences after entering solution was significantly lower than that before entering solution, which should affect the accuracy of DNA hybridization reactions. Therefore, in this study, we propose a new constraint, a triplet-bases unpaired constraint, which can be combined with other constraints to form a new combination constraint. In addition, we combine the Harmony Search algorithm with the Whale Optimization Algorithm (WOA) to present a new algorithm, termed HSWOA, which we used to design DNA sequences that meet the new combination constraint. Finally, compared with previous findings, our result shows that our algorithm not only improves the efficiency of hybridization reactions but also yields a better fitness value.