de Oliveira_2026_J.Chem.Inf.Model__

The natural degradation of synthetic polymers is an extremely slow process, often taking hundreds to thousands of years. The fungus Moniliophthora roreri produces cutinase enzymes, such as MrCut1, MrCut2, and MrCut3, which are capable of depolymerizing synthetic polymers. Although experimental studies have demonstrated that the MrCut1 enzyme can degrade polyethylene succinate (PES), polycaprolactone (PCL), and polyethylene terephthalate (PET), its three-dimensional structure and the atomistic details underlying the binding process with these polymers remain elusive. Here, we present the first atomistic simulations of MrCut1 in complex with PES, PCL, and PET oligomers, providing structural insights into substrate recognition, binding modes, and key interactions driving polymer degradation. Additionally, we evaluated the structural differences among MrCut1, MrCut2, and MrCut3 to assess how these variations affect their affinity for forming enzyme-polymer complexes. Through Free Energy Landscape (FEL) and active site volume analyses, we demonstrate the structural similarity between MrCut1 and MrCut3, as well as their respective volumes for polymer binding at the active site. Our results indicate that the binding affinities of PES, PCL, and PET for MrCut1 are -9.17 +/- 0.49, -9.00 +/- 0.56, and -8.40 +/- 0.49 kcal/mol, respectively. In contrast, these ligands exhibit lower affinities for MrCut3, with values of -7.99 +/- 0.43, -7.95 +/- 0.60, and -7.30 +/- 0.42 kcal/mol, respectively. Furthermore, our findings suggest that the absence of the catalytic triad in MrCut2, together with the lack of a well-formed active site cavity, may result in its inefficient catalytic activity. Finally, we demonstrate, for the first time, the potential of MrCut3 as a biocatalyst, similar to MrCut1, and explore its applicability in the biodegradation of certain synthetic polymers.