For each of the systems, we next performed clustering of the structures present in the trajectories based on RMSD to evaluate and quantify the contribution of different binding modes. For this purpose we used two different algorithms, namely DBSCAN and K-means. The DBSCAN algorithm reveals clusters characterized by a broader average distance between points within each cluster (AvgDist) compared to the K-means analysis. This allows for a more comprehensive overview of the data. However, K-means provides more detailed insights, offering a higher level of specificity in the clustering results. We also performed additional structural analyses of the trajectories which offer further insights into the possible reactive conformations which can enable the primer extension reaction. We start the discussion with the clustering analysis below. Within this discussion we put emphasis on the binding site and the activated dinucleotide intermediates with the naming scheme of the key nucleotides presented in Fig. . In particular, we focused the analyses on the structural arrangements of three key nucleotides, namely the nucleotide located at the 3 ′ -end of the templating strand, the nucleotide of the imidazolium bridged dinucleotide intermediate that is adjacent to it (named simply adjacent), and the remaining nucleotide of the dinucleotide intermediate referred to as terminal (Fig. ).