Quantum chemical and molecular dynamics studies of MUC-1 calix[4,8]arene scaffold based anti-cancer vaccine candidates

Functional antitumor vaccine constructs are the basis for active tumor immunotherapy, which is useful in the treatment of many types of cancers. MUC1 is one key protein for targeting and designing new strategies for multi-component vaccines. Two self-adjuvant tetravalent vaccine candidates were prepared by clustering four or eight PDTRP MUC1 core epitope sequences on calixarene scaffolds. In this work, the different activities of two molecules with calix[4]arene and calix[8]arene skeleton are rationalized. Quantum-Mechanics, Docking and Molecular Dynamics structural optimization were firstly carried out followed by Metadynamics to calculate the energy profiles. Further insights were obtained by molecular fields' complementarity studies. The molecular modelling results are in strong agreement with the experimental in vivo immunogenicity data. In conclusion, the overall data shows that in the designing of anticancer vaccines, the scaffold flexibility has a pivotal role in obtaining a suitable electrostatic, hydrophobic and steric complementarity with the biological target.