Atomistic Insights into gp82 Binding: A Microsecond, Million-Atom Exploration of Host-Cell Invasion.

Chagas disease, caused by the protozoan , affects millions globally, leading to severe cardiac and gastrointestinal complications in its chronic phase. The invasion of host cells by is mediated by the interaction between the parasite's glycoprotein gp82 and the human receptor lysosome-associated membrane protein 2 (LAMP2). While experimental studies have identified a few residues involved in this interaction, a comprehensive molecular-level understanding has been lacking. In this study, we present a 1.44-million-atom computational model of the gp82 complex, including over 3300 lipids, glycosylation sites, and full molecular representations of gp82 and LAMP2, making it the most complete model of a parasite-host interaction to date. Using microsecond-long molecular dynamics simulations and dynamic network analysis, we identified critical residue interactions, including novel regions of contact that were previously uncharacterized. Our findings also highlight the significance of the transmembrane domain of LAMP2 in stabilizing the complex. These insights extend beyond traditional hydrogen bond interactions, revealing a complex network of cooperative motions that facilitate invasion. This study not only confirms key experimental observations but also uncovers new molecular targets for therapeutic intervention, offering a potential pathway to disrupt infection and combat Chagas disease.