Molecular simulation of the structure of folate and antifolates at physiological conditions.

The study is focused on description of folate and several antifolates at physiological conditions. Knowledge of the molecular structure and dynamics is important for understanding their biological activity and therapeutic application. They are modelled in saline by atomistic molecular dynamics simulations and characterized in detail. In addition, quantum chemical calculations are used for determining the electronic structure of the six compounds. All molecules are highly flexible and have similar interactions with water. Specifics are found in some of their local backbone conformations, in the molecular shape, and in the electron density distribution. Most of the ligands have fairly folded geometry and prefer U- and Z-shapes. Two of them are quasi-linear. Key to the molecular shape are the bicyclic fragment, its bridge, and the charge of the terminal amino acid residue. Docking into the active site of folate receptor-α predicts a similar best binding pose for four of the ligands, which requires stretching of pterin and bending of glutamate/ornithine relative to the geometry in saline. The chemical modifications in the antifolates induce local electron density redistribution in comparison to folate, leading to increase of the positive charges of the neighboring fragments. The obtained results would help better tuning of the potential usage of the molecules in new bioactive materials, e.g., as vector-ligands for drug delivery.