The first cyclic tetrapyrrolic intermediates in the heme biosynthetic pathway are generated as porphyrinogens (hexahydroporphyrins), but unlike the aromatic porphyrin nucleus these structures must take on highly distorted conformations. Although this structural requirement is self-evident, these intermediates are often represented as flat structures. In order to gain a better understanding of the enzyme coproporphyrinogen oxidase, which is responsible for the conversion of coproporphyrinogen-III to protoporphyrinogen-IX, conformational studies were performed using molecular dynamics simulations. These studies were carried out on the natural substrate and six synthetic analogues using a Silicon Graphics workstation and the BIOGRAF 3.1 program (Molecular Simulations Inc.). The dynamics were run for 50 ps using the Verlet algorithm and Dreiding force field for each porphyrinogen with 500 quenching steps at 300 and 500 K. The five lowest energy conformations were then used as starting structures for simulations of 200 ps. The data show that the propionic acid side chains critically affect the conformations by hydrogen bonding interactions, and the chair and saddle forms are the most stable conformations. In many cases the B ring propionate moiety, which is known to be crucial for substrate recognition for coproporphyrinogen oxidase, is found to be free of intramolecular hydrogen bonds. However, simulations in the presence of water molecules gave chaise longe conformations and intermolecular interactions overwhelmed other effects for solvated porphyrinogens. Although the local environment will influence the preferred conformations, these MD simulations provide insights into how natural porphyrinogens can behave under physiological conditions.
Molecular dynamics simulations and CD spectroscopy reveal hydration-induced unfolding of the intrinsically disordered LEA proteins COR15A and COR15B from Arabidopsis thaliana
