(451f) Engineered Macromolecules As Inhibitors to Oxidized Low Density Lipoprotein by Macrophage Scavenger Receptors: Simulation of Structure – Function Relationships

Atherosclerosis begins when high levels of circulating low-density lipoproteins (LDL) are transported into the extravascular space and become trapped in the extracellular matrix where they are subject to oxidative modification.  Oxidized LDL causes damage to surrounding endothelial cells and initiates an inflammatory signaling cascade which results in the recruitment of monocytes to the site of injury.  Monocytes differentiate into macrophages that express surface scavenger receptors active in the non-specific uptake of modified LDL.  The excessive uptake of oxidized LDL results in the formation of foam cells which become engorged, die, and subsequently form atherosclerotic plaques.  One possible method to combat plaque formation is through the use of inhibitors to prevent uptake of oxidized LDL by the scavenger receptors.  Tian et al. 2004 [1] developed a class of micelle-forming molecules termed nanolipoblockers (NLB) comprised of a mucic acid head group with attached aliphatic chains and a long polyethylene glycol (PEG) tail used to block uptake of oxidized LDL by scavenger receptors.  In this work, we use coarse-grained molecular dynamics simulations to explore the structural and electrostatic properties of NLBs with the scavenger receptor A (SR-A) to determine optimal interaction and thus inhibition of oxidized LDL uptake.

We use a coarse-grained model based on the MARTINI force field [2] to describe the NLB molecules as well as the collagen-like domain of SR-A containing the binding pocket for oxidized LDL [3].  We include four different NLB structures varying the charge, charge location, and the NLB ability to form micelles.  We find that for NLB molecules containing aliphatic groups near the mucic acid head, micelles form within 300 ns with a micelle diameter of 7.6 – 12.8 nm.  As an indirect assessment of binding affinity, we identified the number of contacts that each type of NLB made with SR-A both at 0.8 nm and 2.0 nm from the receptor.  The number of close contacts (< 0.8 nm) were similar for each NLB, but aligned with experimental trends showing anionic micelle-forming NLBs as the best inhibitors of oxidized LDL uptake.  In calculating the specific contacts between the charged portions of NLBs and the binding pocket of SR-A indicated that the addition of a negative charge on the PEG tails of NLBs did not act to enhance interaction with the important residues of the SR-A, however an anionic charge at the NLB head increased interaction with the positively charged residues of the binding pocket, confirming experimental findings

References:

[1]  Tian L, Yam L, Zhou N, Tat H, and Uhrich KE. Amphiphilic Scorpion-like Macromolecules: Design, Synthesis, and Characterization. Macromolecules. 2004; 37: 538-543.

[2]  Monticelli L, Kandasamy SK, Periole X, Larson RG, Tieleman DP, and Marrink SJ. The MARTINI Coarse-Grained Force Field: Extension to Proteins. J. Chem. Theory and Comput. 2008; 4(5): 819-834.

[3]  Kodama T, Freeman M, Rohrer L, Zabrecky J, Matsudaira P, Krieger M. Type I macrophage scavenger receptor contains alpha-helical and collagen-like coiled coils. Nature. 1990; 343(6258): p. 531-535.