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Published on: July 31, 2019
Atomistic Insights into gp82 Binding: A Microsecond, Million-Atom Exploration of Trypanosoma cruzi Host-Cell Invasion
Raissa S L Rosa1,2,3, Manuela Leal da Silva3,4, Rafael C Bernardi1,2
1Department of Physics, Auburn University, Auburn, Alabama 36849, United States.
Insights
This study reveals critical molecular interactions between Trypanosoma cruzi and human cells, identifying new targets to combat Chagas disease. The research provides a detailed computational model of parasite invasion, crucial for developing novel therapeutics.
Area of Science:
- Molecular biology
- Parasitology
- Computational biophysics
Background:
- Chagas disease, caused by Trypanosoma cruzi, impacts millions worldwide with severe chronic complications.
- Host cell invasion by T. cruzi involves interactions between parasite gp82 and human LAMP2.
- A comprehensive molecular understanding of this interaction has been limited.
Purpose of the Study:
- To elucidate the molecular mechanisms of T. cruzi host cell invasion.
- To build the most complete computational model of a parasite-host interaction to date.
- To identify novel therapeutic targets for Chagas disease.
Main Methods:
- Construction of a 1.44-million-atom computational model of the gp82-LAMP2 complex.
- Microsecond-long molecular dynamics simulations.
- Dynamic network analysis of protein-lipid interactions.
Main Results:
- Identification of critical residue interactions and novel contact regions between gp82 and LAMP2.
- Demonstration of the transmembrane domain of LAMP2's role in complex stabilization.
- Uncovering a network of cooperative motions facilitating T. cruzi invasion.
Conclusions:
- The study provides unprecedented molecular insights into T. cruzi invasion.
- Findings confirm experimental data and reveal new therapeutic targets.
- This research offers a potential strategy to disrupt T. cruzi infection and treat Chagas disease.
Abstract:
Chagas disease, caused by the protozoan Trypanosoma cruzi, affects millions globally, leading to severe cardiac and gastrointestinal complications in its chronic phase. The invasion of host cells by T. cruzi 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 T. cruzi invasion. This study not only confirms key experimental observations but also uncovers new molecular targets for therapeutic intervention, offering a potential pathway to disrupt T. cruzi infection and combat Chagas disease.
