In summary, for reactions with a complexity level close to or below that of glucose, SSI can provide a fast and often accurate prediction of the most stable TSs, while SSIII can provide fairly accurate prediction and with acceptable computational cost (∼ 3 times the cost of SSI in this study). As for much more complex reactions, SSIV is required to achieve an accurate and robust prediction. Even though SSIV is the most time-consuming scheme, it is still much cheaper than a direct search for TS of complex reactions. As a comparison, our previous study utilized up to 20 conformations to locate the lowest energy TS for the cyclic tetrapeptide formation, while in SSIV only four conformations were employed (i.e., 20% of the computational cost).