caused by the update of a. When the full optimization problem is separated, the substantial update of a results in a large error due to the large equilibrium geometry change. Therefore, MDM gradually updates a in the continuous chemical space. It is expected that this also leads to the small displacement of the equilibrium geometry at each design step. Therefore, in practice, the geometry optimization that suitably changes R and approximately solves Eq. ( ) is not performed at all design steps. As the update of a depends on the current equilibrium geometry R, their coupling persists through the iterations. The LCAP discrete optimization performs geometry optimization of nearby candidate molecules in discrete chemical space and subsequently computes the gradient by finite difference. This strategy is costly in our MDM since all the candidate molecules are located at equal distances in the chemical space. Moreover, the error in the discrete update of a should be large.