Molecular dynamics study of the effect of the gamma-Abu insert on the conformational behavior of the glycopeptide dendrimers based on the oligolysine scaffold in N, N'-dimethylformamide.

Glycodendrimers bearing Tn (alpha-D-GalNAc-(1 --> O)-Ser/Thr), an identified tumor-associated carbohydrate antigen, hold promise in the post-surgery treatment of a variety of tumors such as metastatic breast cancer. We used molecular dynamics (MD) techniques to examine structural differences taking place during synthesis of two classes of tetravalent Multiple Antigen Glycopeptides (MAG) that differ only by the gamma-Abu insert in the structure of the oligolysine core. Each of the selected intermediates of the synthesis was modeled, subjected to the 2 ns run in N,N'-dimethylformamide (DMF) and geometrically characterized. We characterized: a) distances of free, or extended termini from the anchor, b) interatomic distances between free or substituted N termini, c) radius of gyration and d) spatial distribution of molecular density. A detailed conformational analysis of 16 glycodendrimers shows the distinct behavior of the inserted vs. non-inserted constructs already during the first steps of the modeled synthesis. It suggests that the character as well as the length of the insert has a major impact on the spatial characteristics and behavior of the dendritic molecules. The inserts can, in principle, increase a tendency of dendrimers to establish a high-density core, which is similar to the effect of a higher generation.