Marcelo Depolo Poleto
@vt.edu
Research Associate - Department of Biochemistry
Virginia Tech
RESEARCH, TEACHING, or OTHER INTERESTS
Biochemistry, Physical and Theoretical Chemistry, Biophysics, Renewable Energy, Sustainability and the Environment
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
Marcelo D. Polêto and Justin A. Lemkul
American Chemical Society (ACS)
The formation of G-quadruplexes (GQs) occurs in guanine-rich sequences of DNA and RNA, producing highly stable and structurally diverse noncanonical nucleic acid structures. GQs play crucial roles in regulating transcription, translation, and replication and maintaining the genome, among others; thus, changes to their structures can lead to diseases such as cancer. Previous studies using polarizable molecular dynamics simulations have shown differences in ion binding properties between telomeric and telomeric repeat-containing RNA GQs despite architectural similarities. Here, we used volume-based metadynamics and repulsive potential simulations in conjunction with polarizable force fields to quantify the impact of ion binding on the GQ dynamics and ion binding free energies. Furthermore, we describe how GQs exert electric fields on their surroundings to link dynamics with variations in the electronic structure. Our findings provide new insights into the energetic, physical, and conformational properties of GQs and expose subtle but important differences between DNA and RNA GQs with the same fold.
Érica Cardoso Valente, Marcelo Depólo Polêto, Thomás Valente de Oliveira, Lucas de Souza Soares, Jane Sélia dos Reis Coimbra, Ana Paula Guimarães, and Eduardo Basílio de Oliveira
Springer Science and Business Media LLC
Débora Cristina Pimentel, Juliana Rodrigues Leopoldo, Leilane Ferreira Teixeira, Marcus Vinícius de Andrade Barros, Ana Paula Martins de Souza, Thiago Souza Onofre, Rayane Luiza de Carvalho, Sara Andrade Machado, Isabelly Gonçalves Messias, Carla Cristina de Souza Pinto,et al.
Elsevier BV
Isadora Cunha Ribeiro, João Victor Badaró de Moraes, Christiane Mariotini-Moura, Marcelo Depolo Polêto, Nancy da Rocha Torres Pavione, Raissa Barbosa de Castro, Izabel Luzia Miranda, Suélen Karine Sartori, Kryssia Lohayne Santos Alves, Gustavo Costa Bressan,et al.
Springer Science and Business Media LLC
Noah Giacon, Ettore Lo Cascio, Darcy S. Davidson, Marcelo D. Polêto, Justin A. Lemkul, Valeria Pennacchietti, Livia Pagano, Carlotta Zamparelli, Angelo Toto, and Alessandro Arcovito
Elsevier BV
Marcelo D. Polêto and Justin A. Lemkul
Springer Science and Business Media LLC
AbstractThe development of accurate protein force fields has been the cornerstone of molecular simulations for the past 50 years. During this period, many lessons have been learned regarding the use of experimental target data and parameter fitting procedures. Here, we review recent advances in protein force field development. We discuss the recent emergence of polarizable force fields and the role of electronic polarization and areas in which additive force fields fall short. The use of automated fitting methods and the inclusion of additional experimental solution data during parametrization is discussed as a means to highlight possible routes to improve the accuracy of force fields even further.
Marcelo D. Polêto and Justin A. Lemkul
Wiley
AbstractWe introduce TUPÃ, a Python‐based algorithm to calculate and analyze electric fields in molecular simulations. To demonstrate the features in TUPÃ, we present three test cases in which the orientation and magnitude of the electric field exerted by biomolecules help explain biological phenomena or observed kinetics. As part of TUPÃ, we also provide a PyMOL plugin to help researchers visualize how electric fields are organized within the simulation system. The code is freely available and can be obtained at https://mdpoleto.github.io/tupa/.
Thomás Valente De Oliveira, Marcelo Depólo Polêto, Samuel Vieira Barbosa, Jane Sélia dos Reis Coimbra, and Eduardo Basílio De Oliveira
Elsevier BV
Pablo R. Arantes, Marcelo D. Polêto, Conrado Pedebos, and Rodrigo Ligabue-Braun
American Chemical Society (ACS)
Thomás Valente De Oliveira, Ana Paula Guimarães, Gustavo Costa Bressan, Elaine Rose Maia, Jane Sélia dos Reis Coimbra, Marcelo Depólo Polêto, and Eduardo Basílio De Oliveira
Informa UK Limited
Abstract The angiotensin-converting enzyme (ACE) plays a key role in blood pressure regulation process, and its inhibition is one of the main drug targets for the treatment of hypertension. Though various peptides from milk proteins are well-known for their ACE-inhibitory capacity, research devoted to understand the molecular bases of such property remain scarce, specifically for such peptides. Therefore, in this work, computational molecular docking and molecular dynamics calculations were performed to enlighten the intermolecular interactions involved in ACE inhibition by six different casein-derived peptides (FFVAPFPEVFGK, FALPQYLK, ALNEINQFYQK, YLGYLEQLLR, HQGLPQEVLNENLLR and NAVPITPTLNR). Two top ranked docking poses for each peptide (one with N- and the other C-terminal peptide extremity oriented towards the ACE active site) were selected for dynamic simulations (50 ns; GROMOS53A6 force field), and the results were correlated to in vitro ACE inhibition capacity. Two molecular features appeared to be essential for peptides to present high ACE inhibition capacity in vitro: i) to interact with the S1 active site residues (Ala354, Glu384, and Tyr523) by hydrogen bonds; ii) to interact with Zn2+ coordinated residues (His383, His387, and Glu411) by short-lenght hydrogen bonds, as observed in the cases of ALNEINQFYQK (IACE = 80.7%), NAVPITPTLNR (IACE = 80.7%), and FALPQYLK (IACE = 79.0%). Regardless of the temporal stability of these strong interactions, they promoted some disruption of Zn2+ tetrahedral coordination during the molecular dynamics trajectories, and were pointed as the main reason for the greatest ACE inhibition by these peptides. On the other hand, peptides with intermediate inhibition capacity (50% < IACE < 45%) interacted mainly by weaker interactions (e.g.: electrostatic and hydrophobic) with the Zn2+ coordinated residues, and were not able to change significantly its tetrahedral coordination structure. These findings may: i) assist the discrimination in silico of “good” and “bad” ACE-inhibitory peptides from other food sources, and/or ii) aid in designing de novo new molecules with ACE-inhibitory capacity. Communicated by Ramaswamy Sarma
Walmir da Silva, Nancy da Rocha Torres, Joice de Melo Agripino, Victor Hugo Ferraz da Silva, Anna Cláudia Alves de Souza, Isadora Cunha Ribeiro, Tatiana Aparecida de Oliveira, Luciana Angelo de Souza, Lethicia Kelly Ramos Andrade, João Victor Badaró de Moraes,et al.
Bentham Science Publishers Ltd.
ENTPDases are enzymes known for hydrolyzing extracellular nucleotides and playing an essential role in controlling the nucleotide signaling via nucleotide/purinergic receptors P2. Moreover, ENTPDases, together with Ecto-5´-nucleotidase activity, affect the adenosine signaling via P1 receptors. These signals control many biological processes, including the immune system. In this context, ATP is considered as a trigger to inflammatory signaling, while adenosine (Ado) induces anti-inflammatory response. The trypanosomatids Leishmania and Trypanosoma cruzi, pathogenic agents of Leishmaniasis and Chagas Disease, respectively, have their own ENTPDases named “TpENTPDases,” which can affect the nucleotide signaling, adhesion and infection, in order to favor the parasite. Besides, TpENTPDases are essential for the parasite nutrition, since the Purine De Novo synthesis pathway is absent in them, which makes these pathogens dependent on the intake of purines and nucleopurines for the Salvage Pathway, in which TpENTPDases also take place. Here, we review information regarding TpNTPDases, including their known biological roles and their effect on the purinergic signaling. We also highlight the roles of these enzymes in parasite infection and their biotechnological applications, while pointing to future developments.
Victor H. Rusu, Denys E. S. Santos, Marcelo D. Poleto, Marcelo M. Galheigo, Antônio T. A. Gomes, Hugo Verli, Thereza A. Soares, and Roberto D. Lins
American Chemical Society (ACS)
Rotational Profiler provides an analytical algorithm to compute sets of classical torsional dihedral parameters by fitting an empirical energy profile to a reference one that can be obtained experimentally or by quantum-mechanical methods. The resulting profiles are compatible with the functional forms in the most widely used biomolecular force fields (e.g., GROMOS, AMBER, OPLS, and CHARMM). The linear least-squares regression method is used to generate sets of parameters that best satisfy the fitting. Rotational Profiler is free to use, analytical, and force field/package independent. The formalism is herein described, and its usage, in an interactive and automated manner, is made available as a Web server at http://rotprof.lncc.br.
Marcelo D Polêto, Bruno I Grisci, Marcio Dorn, and Hugo Verli
Oxford University Press (OUP)
Abstract Motivation The conformational space of small molecules can be vast and difficult to assess. Molecular dynamics (MD) simulations of free ligands in solution have been applied to predict conformational populations, but their characterization is often based on clustering algorithms or manual efforts. Results Here, we introduce ConfID, an analytical tool for conformational characterization of small molecules using MD trajectories. The evolution of conformational sampling and population frequencies throughout trajectories is calculated to check for sampling convergence while allowing to map relevant conformational transitions. The tool is designed to track conformational transition events and calculate time-dependent properties for each conformational population detected. Availability and implementation Toolkit and documentation are freely available at http://sbcb.inf.ufrgs.br/confid Contact marcelo.poleto@ufv.br or bigrisci@inf.ufrgs.br Supplementary information Supplementary data are available at Bioinformatics online.
Thomás Valente De Oliveira, Marcelo Depólo Polêto, Mara Rose De Oliveira, Thaís Jordânia Silva, Edvaldo Barros, Valéria Monteze Guimarães, Maria Cristina Baracat-Pereira, Monique Renon Eller, Jane Sélia dos Reis Coimbra, and Eduardo Basílio De Oliveira
Springer Science and Business Media LLC
Pablo R. Arantes, Conrado Pedebos, Marcelo D. Polêto, Laércio Pol-Fachin, and Hugo Verli
American Chemical Society (ACS)
André S. de Oliveira, Poliana A. R. Gazolla, Ana Flávia C. da S. Oliveira, Wagner L. Pereira, Lívia C. de S. Viol, Angélica F. da S. Maia, Edjon G. Santos, Ítalo E. P. da Silva, Tiago A. de Oliveira Mendes, Adalberto M. da Silva,et al.
Public Library of Science (PLoS)
The West Nile Virus (WNV) NS2B-NS3 protease is an attractive target for the development of therapeutics against this arboviral pathogen. In the present investigation, the screening of a small library of fifty-eight synthetic compounds against the NS2-NB3 protease of WNV is described. The following groups of compounds were evaluated: 3-(2-aryl-2-oxoethyl)isobenzofuran-1(3H)-ones; eugenol derivatives bearing 1,2,3-triazolic functionalities; and indan-1,3-diones with 1,2,3-triazolic functionalities. The most promising of these was a eugenol derivative, namely 4-(3-(4-allyl-2-methoxyphenoxy)-propyl)-1-(2-bromobenzyl)-1H-1,2,3-triazole (35), which inhibited the protease with IC50 of 6.86 μmol L-1. Enzyme kinetic assays showed that this derivative of eugenol presents competitive inhibition behaviour. Molecular docking calculations predicted a recognition pattern involving the residues His51 and Ser135, which are members of the catalytic triad of the WNV NS2B-NS3 protease.
Marcelo D. Polêto, Maura P. Alves, Rodrigo Ligabue-Braun, Monique R. Eller, and Antonio Fernandes De carvalho
Elsevier BV
Pablo R. Arantes, Marcelo D. Polêto, Elisa B. O. John, Conrado Pedebos, Bruno I. Grisci, Marcio Dorn, and Hugo Verli
American Chemical Society (ACS)
Chalcones and flavonoids constitute a large family of plant secondary metabolites that have been explored as a potential source of novel pharmaceutical products. While the simulation of these compounds by molecular dynamics (MD) can be a valuable strategy to assess their conformational properties and so further develop their role in drug discovery, there are no set of force field parameters specifically designed and experimentally validated for their conformational description in condensed phase. So the current work developed a new parameter set for MD simulations of these compounds' main scaffolds under GROMOS force field. We employed a protocol adjusting the atomic charges and torsional parameters to the respective quantum mechanical derived dipole moments and dihedrals rotational profiles, respectively. Experimental properties of organic liquids were used as references to the calculated values to validate the parameters. Additionally, metadynamics simulations were performed to evaluate the conformational space of complex chalcones and flavonoids, while NOE contacts during simulations were measured and compared to experimental data. Accordingly, the employed protocol allowed us to obtain force field parameters that reproduce well the target data and may be expected to contribute in more accurate computational studies on the biological/therapeutical role of such molecules.
Roberta Tesch, Christian Becker, Matthias Philipp Müller, Michael Edmund Beck, Lena Quambusch, Matthäus Getlik, Jonas Lategahn, Niklas Uhlenbrock, Fanny Nascimento Costa, Marcelo D. Polêto,et al.
Wiley
AbstractPIK‐75 is a phosphoinositide‐3‐kinase (PI3K) α‐isoform‐selective inhibitor with high potency. Although published structure–activity relationship data show the importance of the NO2 and the Br substituents in PIK‐75, none of the published studies could correctly determine the underlying reason for their importance. In this publication, we report the first X‐ray crystal structure of PIK‐75 in complex with the kinase GSK‐3β. The structure shows an unusual U‐shaped conformation of PIK‐75 within the active site of GSK‐3β that is likely stabilized by an atypical intramolecular Br⋅⋅⋅NO2 halogen bond. NMR and MD simulations show that this conformation presumably also exists in solution and leads to a binding‐competent preorganization of the PIK‐75 molecule, thus explaining its high potency. We therefore suggest that the site‐specific incorporation of halogen bonds could be generally used to design conformationally restricted bioactive substances with increased potencies.
Nina M Fischer, Marcelo D Polêto, Jakob Steuer, and David van der Spoel
Oxford University Press (OUP)
Abstract The structure of ribonucleic acid (RNA) polymers is strongly dependent on the presence of, in particular Mg2+ cations to stabilize structural features. Only in high-resolution X-ray crystallography structures can ions be identified reliably. Here, we perform molecular dynamics simulations of 24 RNA structures with varying ion concentrations. Twelve of the structures were helical and the others complex folded. The aim of the study is to predict ion positions but also to evaluate the impact of different types of ions (Na+ or Mg2+) and the ionic strength on structural stability and variations of RNA. As a general conclusion Mg2+ is found to conserve the experimental structure better than Na+ and, where experimental ion positions are available, they can be reproduced with reasonable accuracy. If a large surplus of ions is present the added electrostatic screening makes prediction of binding-sites less reproducible. Distinct differences in ion-binding between helical and complex folded structures are found. The strength of binding (ΔG‡ for breaking RNA atom-ion interactions) is found to differ between roughly 10 and 26 kJ/mol for the different RNA atoms. Differences in stability between helical and complex folded structures and of the influence of metal ions on either are discussed.
Marcelo D. Polêto, Victor H. Rusu, Bruno I. Grisci, Marcio Dorn, Roberto D. Lins, and Hugo Verli
Frontiers Media SA
The identification of lead compounds usually includes a step of chemical diversity generation. Its rationale may be supported by both qualitative (SAR) and quantitative (QSAR) approaches, offering models of the putative ligand-receptor interactions. In both scenarios, our understanding of which interactions functional groups can perform is mostly based on their chemical nature (such as electronegativity, volume, melting point, lipophilicity etc.) instead of their dynamics in aqueous, biological solutions (solvent accessibility, lifetime of hydrogen bonds, solvent structure etc.). As a consequence, it is challenging to predict from 2D structures which functional groups will be able to perform interactions with the target receptor, at which intensity and relative abundance in the biological environment, all of which will contribute to ligand potency and intrinsic activity. With this in mind, the aim of this work is to assess properties of aromatic rings, commonly used for drug design, in aqueous solution through molecular dynamics simulations in order to characterize their chemical features and infer their impact in complexation dynamics. For this, common aromatic and heteroaromatic rings were selected and received new atomic charge set based on the direction and module of the dipole moment from MP2/6-31G* calculations, while other topological terms were taken from GROMOS53A6 force field. Afterwards, liquid physicochemical properties were simulated for a calibration set composed by nearly 40 molecules and compared to their respective experimental data, in order to validate each topology. Based on the reliance of the employed strategy, we expanded the dataset to more than 100 aromatic rings. Properties in aqueous solution such as solvent accessible surface area, H-bonds availability, H-bonds residence time, and water structure around heteroatoms were calculated for each ring, creating a database of potential interactions, shedding light on features of drugs in biological solutions, on the structural basis for bioisosterism and on the enthalpic/entropic costs for ligand-receptor complexation dynamics.
Rayane Nunes Lima, Muhammad Faheem, João Alexandre Ribeiro Gonçalves Barbosa, Marcelo Depólo Polêto, Hugo Verli, Fernando Lucas Melo, and Renato Oliveira Resende
Springer Science and Business Media LLC
Rafaella Paola Meneguete Guimarães-Peixoto, Paulo Sérgio Arruda Pinto, Marcus Rebouças Santos, Marcelo Depólo Polêto, Letícia Ferreira Silva, and Abelardo Silva-Júnior
Elsevier BV
Catarina IV Ramos, Flávio Figueira, Marcelo D Polêto, Francisco ML Amado, Hugo Verli, João PC Tomé, and M Graça PMS Neves
Wiley
Electrospray mass spectrometry/mass spectrometry was used to investigate the gas‐phase properties of protonated expanded porphyrins, in order to correlate those with their structure and conformation. We have selected five expanded meso‐pentafluorophenyl porphyrins, respectively, a pair of oxidized/reduced fused pentaphyrins (22 and 24 π electrons), a pair of oxidized/reduced regular hexaphyrins (26 and 28 π electrons) and a regular doubly N‐fused hexaphyrin (28 π electrons).The gas‐phase behavior of the protonated species of oxidized and reduced expanded porphyrins is different. The oxidized species (aromatic Hückel systems) fragment more extensively, mainly by the loss of two HF molecules. The reduced species (Möbius aromatic or Möbius‐like aromatic systems) fragment less than their oxidized counterparts because of their increased flexibility. The protonated regular doubly fused hexaphyrin (non‐aromatic Hückel system) shows the least fragmentation even at higher collision energies.In general, cyclization through losses of HF molecules decreases from the aromatic Hückel systems to Möbius aromatic or Möbius‐like aromatic systems to non‐aromatic Hückel systems and is related to an increase in conformational distortion. Copyright © 2016 John Wiley & Sons, Ltd.
Flávio Figueira, Andreia S. F. Farinha, Paulino V. Muteto, Marcelo D. Polêto, Hugo Verli, M. Teresa S. R. Gomes, Augusto C. Tomé, José A. S. Cavaleiro, and João P. C. Tomé
Royal Society of Chemistry (RSC)
Hexaphyrin-based anion chemosensors are reported for the first time.