Leal da Silva, M. | Search bioRxiv

bioRxiv2024

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

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 parasites 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 3,300 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.

biochemistry↗

bioRxiv2023

Functional annotation hypothetical proteins: a world to be explored in drug development in Trypanosomatids

Hypothetical proteins can provide an alternative pathway for finding potential targets in the development of new drugs due to the fact that many Neglected tropical diseases are caused by Trypanosomatids (Chagas Disease, Leishmaniasis, and Human African Trypanosomiasis). In this work, we focus on applying functional prediction methods based on both sequence and structure to analyze the hypothetical proteins of the pathogenic agents that cause these diseases: T. cruzi (Tcr), T. brucei brucei (Tbr), T. brucei gambiense (Tbg), L. infantum (Lif), L. donovani (Ldo), and L. braziliensis (Lbz). By consulting databases and servers, we have predicted functional domains for twenty-six proteins in Tcr, thirteen in Tbr, fifteen in Tbg, ten in Lif, and one in both Ldo and Lbz. With the goal of developing multi-target therapies, we grouped the domains according to how they are shared among the organisms and investigated those that are shared among more species. By examining the existing literature using specific search strategies, we described what has already been reported for these domains and also analyzed protein structures and sequences, describing mutations among the species and potential drug sites. The published works have unveiled that some of these domains are non-essential for trypanosomatids, like the TRX domain, while others demand further investigation due to a lack of information about metabolic processes (UFC1, Ufm1, ACBP, AAA 18, and Fe-S). Although, we have identified three noteworthy domains that hold promise as targets: TPR, which plays a crucial role in the ciliogenesis process; Nuc deoxyrib tr, essential in purine recycling and recovery mechanisms; and MIX, important for protein targeting and the assembly of complexes such as COX. These three domains are promising targets for drug development due to their conservation, their potential to affect multiple species and their exclusivity.

bioinformatics↗