Characteristics of a Folate Receptor-α Anchored into a Multilipid Bilayer Obtained from Atomistic Molecular Dynamics Simulations

Abstract

Thorough computational description of the properties of membrane-anchored protein receptors, which are important for example in the context of active targeting drug delivery, may be achieved by models representing as close as possible the immediate environment of these macromolecules. An all-atom bilayer, including 35 different lipid types asymmetrically distributed among the two monolayers, is suggested as a model neoplastic cell membrane. One molecule of folate receptor-α (FRα) is anchored into its outer leaflet, and the behavior of the system is explored by atomistic molecular dynamics simulations. The total number of atoms in the model is ∼185 000. Three 1-μs-long simulations are carried out, where physiological conditions (310 K and 1 bar) are maintained with three different pressure scaling schemes. To evaluate the structure and the phase state of the membrane, the density profiles of the system, the average area per lipid, and the deuterium order parameter of the lipid tails are calculated. The bilayer is in liquid ordered state, and the specific arrangement varies between the three trajectories. The changes in the structure of FRα are investigated and are found time- and ensemble-dependent. The volume of the ligand binding pocket fluctuates with time, but this variation remains independent of the more global structural alterations. The latter are mostly “waving” motions of the protein, which periodically approaches and retreats from the membrane. The semi-isotropic pressure scaling perturbs the receptor most significantly, while the isotropic algorithm induces rather slow changes. Maintaining constant nonzero surface tension leads to behavior closest to the experimentally observed one.

Pharmacoresistant Epilepsy in Childhood: Think of the Cerebral Folate Deficiency, a Treatable Disease

“…Thus, we hypothesize that the Cys66Tyr mutation mostly affects protein dynamics which in turn may modulate the function of FRα. Thus, this altered protein most likely leads to an interruption of folate transport into the brain and a depletion of 5-MTHF in the cerebral compartment [27,28].…”

Initial Stages of Spontaneous Binding of Folate-Based Vectors to Folate Receptor-α Observed by Unbiased Molecular Dynamics

“…The whole construct is taken from our recent study. 37 One unbound ligand molecule is then added to it at a random place in the solution (at the side of the outer membrane leaflet, Figure 1). The representative geometries of the free ligand in saline are taken from simulations of the unbound molecules.…”

“…The membrane/receptor model is based on experimental data and is described in detail in our previous work. 37 Just a brief overview of the main characteristics is provided in the Supporting Information (Section Molecular models and computational protocol).…”

“…The system membrane/receptor underwent 1 μs of all-atom MD in our previous study. 37 Due to the liquid ordered phase of the membrane, the spatial arrangement of the lipids is fluid and changes during the course of simulation. Snapshots extracted from this trajectory corresponding to highly populated and well-equilibrated structures are taken as the initial configurations for the current MD simulations.…”

“…Every trajectory for a given ligand starts from a different initial configuration. The first and the second initial configurations share the same receptor structure (extracted at time 199.7 ns of an MD simulation of the unperturbed protein 37 ) but have a different placement of the ligand relative to it. In Conf1, the targeting molecule is closer to the receptor, and in Conf2, it is farther away in the saline.…”