Mechanistic studies by molecular dynamics MD

Atomic-scale simulations of how proteins, membranes and complexes move, and how that motion underpins function.

6 projects

Molecular analysis and production of multi-epitope proteins for the serological diagnosis of dengue

Dengue is an arboviral disease of major global impact, and its serological diagnosis is challenged by cross-reactivity with other flaviviruses, such as Zika virus. In this context, recombinant multi-epitope proteins (RMPs) were developed and optimized for the detection of anti-dengue antibodies. Molecular dynamics and molecular docking analyses are employed to evaluate the structural stability, flexibility, and interactions of RMPs with anti-dengue and anti-Zika antibodies. The proteins were expressed in a heterologous system, purified, and subsequently evaluated for their antigenicity through indirect ELISA assays. Therefore, this study aims to contribute to the development of biomarkers with improved sensitivity and specificity for the serological diagnosis of dengue.

Molecular dynamics analysis of the interaction between the BIBR 1532 inhibitor and the allosteric pocket of the hTERT enzyme

Danielle Jesus Marques

Telomerase is an essential enzyme for telomere maintenance. Telomeres are regions located at the ends of chromosomes that play an important role in maintaining the stability of genetic material. The catalytic subunit hTERT is responsible for the enzymatic activity of telomerase and, therefore, represents an important target for studies investigating the modulation of its activity. This project aims to investigate, through computational approaches, the interaction between the BIBR1532 inhibitor and hTERT, focusing on its possible mode of interaction within an allosteric region of the enzyme. For this purpose, structural analysis and modeling tools, such as PyMOL and Boltz-2, are used for molecular structure preparation, visualization, and prediction. Based on these structures, conformational and dynamic aspects of the protein-inhibitor complex will be evaluated to better understand how interaction with BIBR1532 may influence the structural properties of hTERT.

Team: Amanda Macedo Leandro

Structural and molecular dynamics analysis of the ternary complex model between PrPC, integrin αvβ5, and irisin

Hanna Silva Senna

The project aims to develop a computational model of the interaction between PrPC, integrin αvβ5, and irisin, and to investigate the possibility that the cellular prion protein (PrPC) is involved in the interaction between irisin and integrin αvβ5.

Team: Orientação: Sergio Teixeira Ferreira, Pedro Geraldo Pascutti e Nathália dos Santos Faria

Implicit solvent in the refinement of structural hypotheses for ApoE: Limitations, perspectives and implications for molecular dynamics

Luiz Antônio Freitas

Alzheimer’s disease (AD) is a neurodegenerative disorder in which apolipoprotein E (ApoE), particularly the ApoE4 isoform, plays an important role in disease progression. The Cys112Arg substitution distinguishes ApoE3 from ApoE4 and may alter its stability, conformation, and electrostatic properties. This study aimed to evaluate the impact of this mutation on ApoE structural stability and to establish reproducible protocols for molecular dynamics simulations using implicit solvent models. ApoE3 and ApoE4 models were subjected to 2 μs simulations in triplicate using AMBER 25 and NAMD3 under different dielectric constants (ε = 2, 20, and 80). The tests revealed important limitations in the evaluated models: AMBER 25 showed instability and structural collapse during the simulations, while NAMD3 maintained a high computational cost, contrary to the expectation of greater efficiency. These results highlight the need to optimize implicit solvent protocols for protein studies on long timescales. Future work will investigate the interactions of ApoE3 and ApoE4 with explicit membrane models and expand the benchmarking to coarse-grained and ultra-coarse-grained models using AMBER, NAMD, and OpenMM.

Team: Luiz Antônio Dias da Silva Freitas (IC); Mateus Veiga de Araújo (Coorientador); Pedro Henrique Monteiro Torres (Orientador)

Peptide design based on key residues involved in the interaction between the cellular prion protein (PrPᶜ) and irisin

Nathália dos Santos FariaPhD.

Exerkines are molecules released into the bloodstream by skeletal muscle in response to muscle contraction during physical exercise, exerting beneficial effects on several organs and tissues. Among these molecules, irisin is a myokine generated by the proteolytic cleavage of FNDC5 (fibronectin type III domain-containing protein 5). Previous findings suggest that irisin exerts neuroprotective effects, promoting the rescue of memory and synaptic plasticity in models of Alzheimer's disease (AD). These effects are associated with the activation of intracellular signaling pathways involved in the production of neuroprotective mediators. Irisin-induced signaling can be triggered by its interaction with receptors located at the cell surface, such as integrin αVβ5. However, other cell-surface proteins may also contribute to the modulation of the biological effects mediated by this myokine. In this context, we hypothesize that the cellular prion protein (PrPᶜ) may act as a potential receptor for irisin. Under physiological conditions, PrPᶜ participates in the modulation of intracellular signaling pathways associated with neuroprotection, including the MAPK/ERK and cAMP pathways, which have also been described as targets of irisin-induced signaling. This hypothesis is further supported by the ability of PrPᶜ to interact with proteins containing fibronectin-type domains. Considering that irisin is derived from FNDC5 and contains a fibronectin type III domain, we propose that PrPᶜ may recognize and interact with this myokine. Thus, the interaction between PrPᶜ and irisin could contribute, at least in part, to the neuroprotective effects attributed to irisin. Based on previous findings from our group suggesting the existence of an interaction interface between PrPᶜ and irisin, this study aims to propose irisin-derived peptides based on the identification of key residues involved in the interaction with the cellular prion protein. Classical Mechanics approaches, including molecular docking and molecular dynamics simulations, will be employed to identify structurally stable complexes and characterize the interaction interfaces between PrPᶜ and the proposed peptides. Subsequently, Quantum Mechanics (QM) methods will be applied to investigate the intermolecular interactions established by residues at the interface, as well as their potential involvement in charge-transfer processes. The integration of Classical and Quantum Mechanics approaches will enable a detailed structural and electronic characterization of the complexes, providing a rational basis for selecting peptide candidates with potential to interact with PrPᶜ. The results may guide future experimental studies aimed at evaluating the ability of these peptides to interact with PrPᶜ and modulate signaling pathways associated with neuroprotection.

Team: Nathália dos Santos Faria, Pedro Pascutti, Sérgio Ferreira (externo)

Investigation of the confinement of functional motions within intrinsic electric fields for the optimization of enzymatic catalysis via modeling and molecular dynamics

Samuel de Araujo Cruz SilvaBSc.

Investigation of the influence of the intrinsic electric field on enzyme conformational dynamics using modeling and molecular dynamics simulations, evaluating how changes in electric charge distribution-induced by point mutations-affect functional motions, structural stability, and the conformational landscape.

Team: Samuel de Araujo Cruz Silva - Pedro Geraldo Pascutti