The Effect of pH to The Interaction between Folic Acid and Folate Receptor Alpha: Molecular Dynamics Study

Cancer is one of the major health problems in the world. Early detection using Magnetic Resonance Imaging (MRI) for the presence of cancer cells could improve the successful rate of treatment. For this reason, a selective contrast agent is required to improve the accuracy of cancer diagnosis. Many cancer cells overexpress the folate receptor alpha (FRA) on its surface. Therefore, the substrate of FRA, folic acid, can be used to develop a selective contrast agent such as Gd-DTPA-folate. However, it is worth noting that the slightly acidic pH in cancer cell could change the conformation of ligand binding site of FRA, thus lowering the affinity of folic acid-based contrast agent. Although the crystal structure of FRA in low pH has been solved, but the mechanism of decreasing affinity of folic acid is still not clear. Therefore, this work aims to study the structural change of FRA in low pH and to investigate the molecular interactions of folic acid and Gd-DTPA- folate to the FRA at normal and acidic pH using molecular dynamics simulations. A crystal structure of folic acid in complex with FRA was used as a template for simulations. The interaction energies were calculated using MM/GBSA method. As a result, the protonated Asp81 in the ligand binding site of FRA repulsed the pterin ring of folic acid. Interestingly, Gd-DTPA-folate was predicted to stabilize its interaction with FRA in low-pH as compared to the normal pH. It is hoped that this study could provide insight into the development of selective contrast agent for cancer.