Exploring the Desumoylation Process of SENP1: A Study Combined MD Simulations with QM/MM Calculations on SENP1-SUMO1-RanGAP1

The small ubiquitin-related modifier (SUMO)-specific protease (SENP) processes SUMOs to mature forms and deconjugates them from various modified substrates. Loss of the equilibrium from desumoylation catalyzed by abnormal SENP1 is associated with cancers and transcription factor activity. In spite of the significant role of SENP1, the molecular basis of its desumoylation remains unclear. Here, MD simulations and QM/MM methods are combined to investigate the catalytic mechanism of desumoylation. The results showed that substrate SUMO1-RanGAP1 fitted into the catalytic pocket of SENP1 by the break of internal hydrophobic interactions and the isomerization of isopeptide from <i>trans</i> to <i>cis</i>. After that, the nucleophilic sulfur anion of Cys603 in SENP1 attacked the carbonyl carbon of Gly97 of SUMO1 to trigger the reaction, and then a tetrahedral intermediate and an acyl-enzyme intermediate were generated in turn, leading to the final release of enzyme SENP1 and two products, free SUMO1 and RanGAP1. In the process, nucleophilic attack was identified as the rate-determining step with a potential energy barrier of 20.2 kcal/mol. These results are in agreement with experimental data from mutagenesis and other experiments. Our findings elucidate the catalytic mechanism of SENP1 with its substrate and may provide a better understanding of SENP desumoylation. In particular, we have identified key residues in SENP1 needed for desumoylation that might be beneficial for the design of novel inhibitors of SENP1-related diseases