Coarse Grained Molecular Dynamics of Engineered Macromolecules for the Inhibition of Oxidized Low De

Time-lapse trajectories illustrating the self-assembly processes of NLBs. Each system began with 25 randomly distributed NLB unimers and proceeded for 800 ns. NLBs containing aliphatic chains (1CM, 0CM, and 1CP) assembled into micelles within 200 – 400 ns whereas PEG-COOH remained as unimers. The particles colored red are the PEG tails and those colored in cyan are the mucic acid and the aliphatic groups

Atherosclerosis is a condition resulting from the accumulation of oxidized low-density lipoproteins (oxLDL) 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 3 of the 4 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 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. In 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 uptake of oxLDL.