Molecular disruption of pulmonary surfactant proteins by airborne pollutants: an integrative in-silico toxicology approach.

Abstract

Objective: Pulmonary surfactant proteins (SP-A, SP-B, SP-C, and SP-D) are essential regulators of alveolar surface tension and pulmonary immune defense, forming a critical frontline barrier against airborne xenobiotics. This study aimed to evaluate the molecular interactions between environmentally prevalent airborne pollutants and human surfactant proteins.

Materials and methods: A multi-tiered computational framework assessed interactions between 87 airborne pollutants and surfactant proteins. Structure-based molecular docking using AutoDock Vina identified benzo[a]pyrene and crotonic acid as highest-affinity ligands (binding energies up to -8.1 kcal/mol). The top ligands underwent 200 ns molecular dynamics simulations with SP-A, SP-B, SP-C, and SP-D using the CHARMM36 force field in GROMACS. Structural metrics (RMSD, RMSF, SASA, and Rg), principal component analysis (PCA), and MM-GBSA binding free energy calculations were performed.

Results and discussion: Analyses demonstrated sustained ligand-protein interactions and moderate conformational shifts, particularly within SP-A and SP-C domains. PCA revealed ligand-induced conformational changes, while MM-GBSA confirmed thermodynamic favorability (ΔGbind -26.5 to -32.8 kcal/mol). These findings suggest a novel mechanism of respiratory toxicity via molecular disruption of surfactant proteins.

Conclusions: This integrated in-silico approach highlights pollutant-induced surfactant protein alterations as potential biomarkers of pulmonary toxicant exposure and underscores the need for experimental validation and further mechanistic studies.