Coarse Grained Molecular Dynamics of Engineered Macromolecules for the Inhibition of Oxidized Low-Density Lipoprotein Uptake by Macrophage Scavenger Receptors

• Published in: Biomacromolecules Vol. 14; no. 8; pp. 2499 - 2509
• Main Authors: Tomasini, Michael D, Zablocki, Kyle, Petersen, Latrisha K, Moghe, Prabhas V, Tomassone, M. Silvina
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 12.08.2013
• Subjects: Antimetabolites - chemical synthesis; Antimetabolites - pharmacology; Applied sciences; Binding Sites; Biological and medical sciences; Biological properties; Cells, Cultured; Drug Evaluation, Preclinical; Exact sciences and technology; General and cellular metabolism. Vitamins; Humans; Lipoproteins, LDL - antagonists & inhibitors; Lipoproteins, LDL - metabolism; Macrophages - drug effects; Macrophages - metabolism; Medical sciences; Micelles; Molecular Conformation; Molecular Dynamics Simulation; Organic polymers; Pharmacology. Drug treatments; Physicochemistry of polymers; Polyethylene Glycols - chemical synthesis; Polyethylene Glycols - pharmacology; Properties and characterization; Protein Binding; Scavenger Receptors, Class A - chemistry; Scavenger Receptors, Class A - metabolism; Sugar Acids - chemical synthesis; Sugar Acids - pharmacology; Branched polymer; Computer simulation; Molecular dynamics method; Experimental study; In vitro; Biological activity; Uptake; Dose activity relation; Ethylene oxide polymer; Intermolecular interaction; Lipoprotein LDL; Inhibition; Antilipemic agent; Macrophage; Amphiphilic polymer
• ISSN: 1525-7797; 1526-4602
• DOI: 10.1021/bm301764x

Atherosclerosis is a condition resulting from the accumulation of oxidized low-density lipoproteins (oxLDLs) in arterial walls. Previously developed macromolecules consisting of alkyl chains and polyethylene glycol (PEG) on a mucic acid backbone, termed nanolipoblockers (NLBs) are hypothesized to mitigate the uptake of oxLDL by macrophage scavenger receptors. In this work, we developed a coarse grained model to characterize the interactions between NLBs with a segment of human scavenger receptor A (SR-A), a key receptor domain that regulates cholesterol uptake and foam cell conversion of macrophages, and studied NLB ability to block oxLDL uptake in PBMC macrophages. We focused on four different NLB configurations with variable molecular charge, charge location, and degree of NLB micellization. Kinetic studies showed that three of the four NLBs form micelles within 300 ns and of sizes comparable to literature results. In the presence of SR-A, micelle-forming NLBs interacted with the receptor primarily in an aggregated state rather than as single unimers. The model showed that incorporation of an anionic charge near the NLB mucic acid head resulted in enhanced interaction with the proposed binding pocket of SR-A compared to uncharged NLBs. By contrast, NLBs with an anionic charge located at the PEG tail showed no interaction increase as NLB aggregates were predominately observed to interact away from the oxLDL binding site. Additionally, using two different methods to assess the number of contacts that each NLB type formed with SR-A, we found that the rank order of contacts coincided with our experimental flow cytometry results evaluating the ability of the different NLBs to block the uptake of oxLDL.