because of the orthogonal invariance of 𝐂 . From Eq. 8, the A-optimal design has the lowest sum of variances and is responsive to a reduction in the arithmetic mean of the parameter uncertainties. For A-optimal designs, the total variance is reduced by more connections to the highest similarity ligands (Results), often resulting in a branched topology. The D-optimal design responds to a reduction in the geometric mean of the parameter uncertainties. This promotes less extreme values of 𝜆 𝑖 (𝐂) and increases cycles (Results). In some cases, multiple degenerate designs could satisfy the conditions in Eq. 8. So, we use 𝒢 * to mean the solution found through optimization. Optimization can be repeated from unique seed designs to select the optimal solution.