A second, less commonly employed method, to reveal the reaction coordinates in biomolecular studies, is the time-lagged Independent Component Analysis (tICA). While PCA focuses on the largest variance in the dataset, which generally corresponds to fast molecular motion, tICA can be used to separate and extract the internal coordinates which exhibit the strongest time-correlations for a chosen lag time, thus revealing slow movements in the system. The tICA performed on the reduced internal coordinates set, resulted in a good separation of the product and educt states, mainly across the first independent component (IC1), as shown in Figure , where the values of IC1 and IC2 are plotted separately, and Figure , where they are plotted against each other and the structures are color-coded according to their labels. Yet the transition state ensemble cannot be fully separated from the educts. When taking into consideration IC2 (Figure and 3B), we observe a broad distribution of the product ensemble, indicating significant conformational flexibility. The contributions to ICs can be traced down, by relating the contribution strength (Figure ) to the degree of freedom it corresponds to (Figure IC1 reveals the changes at the reaction centre related the Cu adopting a planar configuration upon product formation, as evident for example by the Phena-Cu-Br angle (1 st column) that increases with decreasing IC1 (1 st column). Of particular interest are the increase in Cu-C and the Cu-N bond distances (1 st column) when going to the products, accompanied to a shortening of C-N (5 th column), as indicative of the reductive elimination step, as well as the strong contributions of the distances between the aniline product moiety (NPh) and the c0, c2, c6 and c7 calixarene units (4 th column). The later hint at the formation of π-π interactions between the cage and the product. Additionally, a tilting of the calixarene cage can be inferred, when looking at the changes in the Phena-Cu-cX and Phena-Cu-oX angles: For example, Phena-Cu-O2, Phena-Cu-O3, and Phena-Cu-O4 (1 st column), all located at the lower rim of the calixarene cage (Figure (insert)), anticorrelate with IC1, hence, they increase when the product is formed (decreasing IC1), whereas those on the lower rim of the cage, such as Phena-Cu-c6 (4 th column) as well as Phena-Cu-O7 and Phena-Cu-c7 (5 th column) decrease. This finding indicates the movement in opposing directions, when looking at units on opposite sides of the cage. IC2 acts to separate various conformers within the product ensemble, where we can see a difference in the position of the product in the calixarene cage, inferred from the strength of the contributions of the product-calixarene unit distances.