Molecular dynamics simulations to explore the structure and rheological properties of normal and hyperconcentrated airway mucus

AG Ford and XZ Cao and MJ Papanikolas and T Kato and RC Boucher and MR Markovetz and DB Hill and R Freeman and MG Forest, STUDIES IN APPLIED MATHEMATICS, 147, 1369-1387 (2021).

DOI: 10.1111/sapm.12433

We develop the first molecular dynamics model of airway mucus based on the detailed physical properties and chemical structure of the predominant gel-forming mucin MUC5B. Our airway mucus model leverages the LAMMPS open-source code , based on the statistical physics of polymers, from single molecules to networks. On top of the LAMMPS platform, the chemical structure of MUC5B is used to superimpose proximity-based, noncovalent, transient interactions within and between the specific domains of MUC5B polymers. We explore feasible ranges of hydrophobic and electrostatic interaction strengths between MUC5B domains with 9 nm spatial and 1 ns temporal resolution. Our goal here is to propose and test a mechanistic hypothesis for a striking clinical observation with respect to airway mucus: a 10-fold increase in nonswellable, dense structures called flakes during progression of cystic fibrosis disease. Among the myriad possible effects that might promote self-organization of MUC5B networks into flake structures, we hypothesize and confirm that the clinically confirmed increase in mucin concentration, from 1.5 to 5 mg/ml, alone is sufficient to drive the structure changes observed with scanning electron microscopy images from experimental samples. We postprocess the LAMMPS simulated data sets at 1.5 and 5 mg/ml, both to image the structure transition and compare with scanning electron micrographs and to show that the 3.33-fold increase in concentration induces closer proximity of interacting electrostatic and hydrophobic domains, thereby amplifying the proximity-based strength of the interactions.

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