RESUMO
Essential oils (EOs) are natural products currently used to control arthropods, and their interaction with insect odorant-binding proteins (OBPs) is fundamental for the discovery of new repellents. This in silico study aimed to predict the potential of EO components to interact with odorant proteins. A total of 684 EO components from PubChem were docked against 23 odorant binding proteins from Protein Data Bank using AutoDock Vina. The ligands and proteins were optimized using Gaussian 09 and Sybyl-X 2.0, respectively. The nature of the protein-ligand interactions was characterized using LigandScout 4.0, and visualization of the binding mode in selected complexes was carried out by Pymol. Additionally, complexes with the best binding energy in molecular docking were subjected to 500 ns molecular dynamics simulations using Gromacs. The best binding affinity values were obtained for the 1DQE-ferutidine (-11 kcal/mol) and 2WCH-kaurene (-11.2 kcal/mol) complexes. Both are natural ligands that dock onto those proteins at the same binding site as DEET, a well-known insect repellent. This study identifies kaurene and ferutidine as possible candidates for natural insect repellents, offering a potential alternative to synthetic chemicals like DEET.
Assuntos
Simulação de Acoplamento Molecular , Óleos Voláteis , Receptores Odorantes , Receptores Odorantes/química , Receptores Odorantes/metabolismo , Óleos Voláteis/química , Animais , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Simulação de Dinâmica Molecular , Repelentes de Insetos/química , Ligantes , Relação Quantitativa Estrutura-AtividadeRESUMO
Nerve agents are organophosphates (OPs) that act as potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of acetylcholine. After inhibition, a dealkylation reaction of the phosphorylated serine, known as the aging of AChE, can occur. When aged, reactivators of OP-inhibited AChE are no longer effective. Therefore, the realkylation of aged AChE may offer a pathway to reverse AChE aging. In this study, molecular modeling was conducted to propose new ligands as realkylators of aged AChE. We applied a methodology involving docking and quantum mechanics/molecular mechanics (QM/MM) calculations to evaluate the resurrection kinetic constants and ligand interactions with OP-aged AChE, comparing them to data found in the literature. The results obtained confirm that this method is suitable for predicting kinetic and thermodynamic parameters of ligands, which can be useful in the design and selection of new and more effective ligands for AChE realkylation.
Assuntos
Acetilcolinesterase , Inibidores da Colinesterase , Indolquinonas , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Cinética , Indolquinonas/química , Simulação de Acoplamento Molecular , Ligantes , Termodinâmica , Modelos Moleculares , Humanos , Simulação de Dinâmica MolecularRESUMO
The search for bioactive compounds in natural products holds promise for discovering new pharmacologically active molecules. This study explores the anti-inflammatory potential of açaí (Euterpe oleracea Mart.) constituents against the NLRP3 inflammasome using high-throughput molecular modeling techniques. Utilizing methods such as molecular docking, molecular dynamics simulation, binding free energy calculations (MM/GBSA), and in silico toxicology, we compared açaí compounds with known NLRP3 inhibitors, MCC950 and NP3-146 (RM5). The docking studies revealed significant interactions between açaí constituents and the NLRP3 protein, while molecular dynamics simulations indicated structural stabilization. MM/GBSA calculations demonstrated favorable binding energies for catechin, apigenin, and epicatechin, although slightly lower than those of MCC950 and RM5. Importantly, in silico toxicology predicted lower toxicity for açaí compounds compared to synthetic inhibitors. These findings suggest that açaí-derived compounds are promising candidates for developing new anti-inflammatory therapies targeting the NLRP3 inflammasome, combining efficacy with a superior safety profile. Future research should include in vitro and in vivo validation to confirm the therapeutic potential and safety of these natural products. This study underscores the value of computational approaches in accelerating natural product-based drug discovery and highlights the pharmacological promise of Amazonian biodiversity.
Assuntos
Anti-Inflamatórios , Inflamassomos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Inflamassomos/antagonistas & inibidores , Inflamassomos/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Euterpe/química , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologiaRESUMO
Absolute binding free energy (ABFE) calculations with all-atom molecular dynamics (MD) have the potential to greatly reduce costs in the first stages of drug discovery. Here, we introduce BAT2, the new version of the Binding Affinity Tool (BAT.py), designed to combine full automation of ABFE calculations with high-performance MD simulations, making it a potential tool for virtual screening. We describe and test several changes and new features that were incorporated into the code, such as relative restraints between the protein and the ligand instead of using fixed dummy atoms, support for the OpenMM simulation engine, a merged approach to the application/release of restraints, support for cobinders and proteins with multiple chains, and many others. We also reduced the simulation times for each ABFE calculation, assessing the effect on the expected robustness and accuracy of the calculations.
Assuntos
Simulação de Dinâmica Molecular , Proteínas , Termodinâmica , Proteínas/química , Proteínas/metabolismo , Ligantes , Ligação Proteica , SoftwareRESUMO
In this paper the effects on the interaction of highly positively charged substitution-inert platinum polynuclear complexes (SI-PPCs) with negatively charged DNA and heparin are examined and compared by theoretical chemistry methods. Electrostatic and hydrogen bonding interactions contribute to the overall effects on the biomolecule. Root Mean Square (RMS) deviation, Solvent Accessible Surface, RMS fluctuation, and interaction analysis all confirm similar effects on both biomolecules, dictated predominantly by the total positive charge and total number of hydrogen bonds formed. Especially, changes in structural parameters suggesting condensation and reduction of available surface area will reduce or prevent normal protein recognition and may thus potentially inhibit biological mechanisms related to apoptosis (DNA) or reduced vascularization viability (HEP). Thermodynamic analyses supported these findings with favourable interaction energies. The comparison of DNA and heparin confirms the general intersectionality between the two biomolecules and confirms the intrinsic dual-nature function of this chemotype. The distinction between the two-limiting mode of actions (HS or DNA-centred) could reflect an intriguing balance between extracellular (GAG) and intracellular (DNA) binding and affinities. The results underline the need to fully understand GAG-small molecule interactions and their contribution to drug pharmacology and related therapeutic modalities. This report contributes to that understanding.
Assuntos
DNA , Simulação de Dinâmica Molecular , Espermidina , Espermina , Espermina/química , DNA/química , DNA/metabolismo , Espermidina/química , Espermidina/metabolismo , Heparina/química , Heparina/metabolismo , Termodinâmica , Ligação de Hidrogênio , Eletricidade EstáticaRESUMO
The present study utilizes molecular dynamics simulations to examine how different anions compete for protein solvation in aqueous solutions of ionic liquids (ILs). Ubiquitin is used as model protein and studied in IL mixtures sharing the same cation, 1-ethyl-3-methylimidazolium (EMIM), and two different anions in the same solution, from combinations of dicyanamide (DCA), chloride (Cl), nitrate (NO3), and tetrafluoroborate (BF4). Our findings reveal that specific interactions between anions and the protein are paramount in IL solvation, but that combinations of anions are not additive. For example, DCA exhibits a remarkable ability to form hydrogen bonds with the protein, resulting in a significantly stronger preferential binding to the protein than other anions. However, the combination of DCA with NO3, which also forms hydrogen bonds with the protein, results in a smaller preferential solvation of the protein than the combination of DCA with chloride ions, which are weaker binders. Thus, combining anions with varying affinities for the protein surface modulates the overall ion accumulation through nonadditive mechanisms, highlighting the importance of the understanding of competition for specific interaction sites, cooperative binding, bulk-solution affinity, and overall charge compensations, on the overall solvation capacity of the solution. Such knowledge may allow for the design of novel IL-based processes in biotechnology and material science, where fine-tuning protein solvation is crucial for optimizing performance and functionality.
Assuntos
Ânions , Líquidos Iônicos , Simulação de Dinâmica Molecular , Água , Líquidos Iônicos/química , Ânions/química , Água/química , Ubiquitina/química , Ligação de Hidrogênio , Solubilidade , Imidazóis/químicaRESUMO
The α9α10 nicotinic cholinergic receptor (nAChR) is a ligand-gated pentameric cation-permeable ion channel that mediates synaptic transmission between descending efferent neurons and mechanosensory inner ear hair cells. When expressed in heterologous systems, α9 and α10 subunits can assemble into functional homomeric α9 and heteromeric α9α10 receptors. One of the differential properties between these nAChRs is the modulation of their ACh-evoked responses by extracellular calcium (Ca2+). While α9 nAChRs responses are blocked by Ca2+, ACh-evoked currents through α9α10 nAChRs are potentiated by Ca2+ in the micromolar range and blocked at millimolar concentrations. Using chimeric and mutant subunits, together with electrophysiological recordings under two-electrode voltage-clamp, we show that the TM2-TM3 loop of the rat α10 subunit contains key structural determinants responsible for the potentiation of the α9α10 nAChR by extracellular Ca2+. Moreover, molecular dynamics simulations reveal that the TM2-TM3 loop of α10 does not contribute to the Ca2+ potentiation phenotype through the formation of novel Ca2+ binding sites not present in the α9 receptor. These results suggest that the TM2-TM3 loop of α10 might act as a control element that facilitates the intramolecular rearrangements that follow ACh-evoked α9α10 nAChRs gating in response to local and transient changes of extracellular Ca2+ concentration. This finding might pave the way for the future rational design of drugs that target α9α10 nAChRs as otoprotectants.
Assuntos
Cálcio , Receptores Nicotínicos , Animais , Ratos , Acetilcolina/metabolismo , Acetilcolina/farmacologia , Sequência de Aminoácidos , Sítios de Ligação , Cálcio/metabolismo , Simulação de Dinâmica Molecular , Técnicas de Patch-Clamp , Subunidades Proteicas/metabolismo , Subunidades Proteicas/genética , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/química , Xenopus laevisRESUMO
The enzyme PETase fromIdeonella sakaiensis (IsPETase) strain 201-F6 can catalyze the hydrolysis of polyethylene terephthalate (PET), mainly converting it into mono(2-hydroxyethyl) terephthalic acid (MHET). In this study, we used quantum mechanics/molecular mechanics (QM/MM) simulations to explore the molecular details of the catalytic reaction mechanism of IsPETase in the formation of MHET. The QM region was described with AM1d/PhoT and M06-2X/6-31+G(d,p) potential. QM/MM simulations unveil the complete enzymatic PET hydrolysis mechanism and identify two possible reaction pathways for acylation and deacylation steps. The barrier obtained at M06-2X/6-31+G(d,p)/MM potential for the deacylation step corresponds to 20.4 kcal/mol, aligning with the experimental value of 18 kcal/mol. Our findings indicate that deacylation is the rate-limiting step of the process. Furthermore, per-residue interaction energy contributions revealed unfavorable contributions to the transition state of amino acids located at positions 200-230, suggesting potential sites for targeted mutations. These results can contribute to the development of more active and selective enzymes for PET depolymerization.
Assuntos
Polietilenotereftalatos , Teoria Quântica , Polietilenotereftalatos/química , Polietilenotereftalatos/metabolismo , Simulação de Dinâmica Molecular , Burkholderiales/enzimologia , Burkholderiales/metabolismo , Hidrólise , Biodegradação Ambiental , Biocatálise , AcilaçãoRESUMO
CONTEXT: Molecularly imprinted polymers (MIPs) have promising applications as synthetic antibodies for protein and peptide recognition. A critical aspect of MIP design is the selection of functional monomers and their adequate proportions to achieve materials with high recognition capacity toward their targets. To contribute to this goal, we calibrated a molecular dynamics protocol to reproduce the experimental trends in peptide recognition of 13 pre-polymerization mixtures reported in the literature for the peptide toxin melittin. METHODS: Three simulation conditions were tested for each mixture by changing the box size and the number of monomers and cross-linkers surrounding the template in a solvent-explicit environment. Fully atomistic MD simulations of 350 ns were conducted with the AMBER20 software, with ff19SB parameters for the peptide, gaff2 parameters for the monomers and cross-linkers, and the OPC water model. Template-monomer interaction energies under the LIE approach showed significant differences between high-affinity and low-affinity mixtures. Simulation systems containing 100 monomers plus cross-linkers in a cubic box of 90 Å3 successfully ranked the mixtures according to their experimental performance. Systems with higher monomer densities resulted in non-specific intermolecular contacts that could not account for the experimental trends in melittin recognition. The mixture with the best recognition capacity showed preferential binding to the 13-26-α-helix, suggesting a relevant role for this segment in melittin imprinting and recognition. Our findings provide insightful information to assist the computational design of molecularly imprinted materials with a validated protocol that can be easily extended to other templates.
Assuntos
Simulação de Dinâmica Molecular , Peptídeos , Peptídeos/química , Meliteno/química , Polimerização , Polímeros Molecularmente Impressos/química , Impressão Molecular/métodosRESUMO
CONTEXT: Geometrical knots are rare structural arrangements in proteins in which the polypeptide chain ties itself into a knot, which is very intriguing due to the uncertainty of their impact on the protein properties. Presently, classical molecular dynamics is the most employed technique in the few studies found on this topic, so any information on how the presence of knots affects the reactivity and electronic properties of proteins is even scarcer. Using the electronic structure methods and quantum chemical descriptors analysis, we found that the same amino-acid residues in the knot core have statistically larger values for the unknotted protein, for both hard-hard and soft-soft interaction descriptors. In addition, we present a computationally feasible protocol, where we show it is possible to separate the contribution of the geometrical knot to the reactivity and other electronic structure properties. METHODS: In order to investigate these systems, we used PRIMoRDiA, a new software developed by our research group, to explore the electronic structure of biological macromolecules. We evaluated several local quantum chemical descriptors to unveil relevant patterns potentially originating from the presence of the geometrical knot in two proteins, belonging to the ornithine transcarbamylase family. We compared several sampled structures from these two enzymes that are highly similar in both tertiary structure and function, but one of them has a knot whereas the other does not. The sampling was carried out through molecular dynamics simulations using ff14SB force field along 50 ns, and the semiempirical convergence was performed with PM7 Hamiltonian.