n the last couple of decades, growing attention was drawn to proteins having an entangled topology in their native ensemble. Their folding events are characterized by topological frustration and kinetic traps which pose challenges in their study. Nevertheless, some folding features can be inferred by simple topological descriptors. Baiesi and colleagues [1] introduced a linking number-inspired descriptor called Gaussian Entanglement. Remarkably, up to 32% of proteins domains have a topologically entangled motif, therefore it is valuable to understand how these structures keep under control the entanglement during folding. Using Molecular Dynamics to probe folding events of a test case protein having an entangled topology (the Type III Antifreeze Protein RD1), within a structure-based and Alpha-Carbon representation, we observed that native contacts related to the entanglement tend to form in the late stages of the folding. These results are in agreement with the hypothesis that the protein evolved to postpone the formation of the so-called “entangled contacts”. As for future outlooks, a large-scale analysis of these entangled structures [2] suggests a possible key role of cotranslation in facilitating the protein to find its native ensemble. [1] Baiesi, M.; Orlandini, E.; Trovato, A.; Seno, F. Scientific Reports 2016, 6, 33872 [2] Baiesi, M.; Orlandini, E.; Seno, F.; Trovato, A. Scientific Reports 2019, 9, 8426