Computer simulation of the spatial structures of MUC1 peptides capable of inhibiting apoptosis

The identification of new effective apoptosis inhibitors plays an important role in the development of drugs for the treatment of various disorders, including neurogenerative diseases. Apoptosis is initiated via the formation of macromolecular protein complexes. These complexes exert the activation of caspases, which are key regulators and executors of apoptosis. The death inducing signaling complex, (DISC) plays a central role in the induction of the extrinsic apoptosis pathway. The adaptor protein FADD is the core component of the DISC that is essential for caspase activation at the DISC and subsequent apoptosis initiation. Therefore, inhibitors of FADD may serve as candidate drugs inhibiting apoptosis. Furthermore, the study of the mechanisms of action of these inhibitors is of great interest for understanding the signal transduction pathways of apoptosis. It has been reported that the mucin type 1 glycoprotein (MUC1) is a natural protein inhibitor of FADD. In particular, two fragments of the primary structure of the cytoplasmic domain of MUC1 (MUC1-CD) are capable of inhibiting the binding of procaspase 8 to FADD. However, the 3D structure of MUC1 has not been obtained yet. This significantly complicates the rational design of potential drugs based on the peptides derived from the MUC1 structure. The aim of the present study was in silico prediction of the 3D structures of MUC1-CD peptides corresponding to protein fragments 120 and 4672, as well as the analysis of their conformational properties. The special attention was placed on the MUC1-CD (46-72) peptide, which is able to bind to FADD. By using the method of molecular dynamics in implicit water it was shown that the structure of the peptide MUC1-CD (46-72) is similar to the three-dimensional structures of at least four fragments of caspase 8. These results indicate that the molecular mechanism of the inhibitory action of the peptide can be explained by the competitive binding of MUC1 to FADD due to the structural and conformational similarity to fragments of the caspase 8 DEDs.