Modelització de les diverses glicoformes de l’antigen prostàtic específic (PSA)

Abstract

The prostate-specific antigen, known as PSA, is a glycoprotein that is secreted in the prostatic epithelial cells and is expressed both in benign and malignant cells. It is used as a marker of the prostate cancer but has some limitations as false positives since other diseases can increase PSA levels too. The solution to this reliability problem can be found in the PSA glycosylation. Studies have shown that in cancer, the composition and connectivity of the sugar chain change as well as the presence of fucose is reduced. Studying this changes can lead to the development of more efficient markers to distinguish cases of prostate cancer from other diseases such as benign prostatic hyperplasia. In the work presented a PSA modeling has been made as well as a computational simulation of different glycoforms generated. The original structure of the protein has been obtained from the PDB (3QUM) and has been modified to obtain three different glycoforms. The first glycoform (G1) has been deglycosylated while the other two glycoforms (G2 and G3) have been glycosylated with a biantennary glycosylation. The difference between the two biantennary glycoforms is in the presence or absence of fucose. To perform the computational simulation of the proteins, classical molecular mechanics has been used as well as the molecular dynamics. After completing the dynamics, an analysis of the rmsd, to study the convergence of the simulations, and the hydrogen bonds, to observe the relevant interactions for protein stability, has been made. The hydrogen bonds distances have also been analyzed. The time of the three simulations that have been made is comprised between 38 and 57 ns. In the elapsed time, the simulations have not converged and proteins have not achieved the most stable conformation. Concerning the hydrogen bonds analysis, two interactions have been found in the glycoform with fucose that are stronger that the observed in the glycoform without fucose. Finally, the analysis of the hydrogen bonds distances has showed that the G2 and G3 suffer a conformational change toward the end of the simulation