molecular mechanics calculations
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2021 ◽  
Author(s):  
Pedro R. Figueiredo ◽  
Ricardo D. González ◽  
Alexandra T.P. Carvalho

Increased hydrolysis of cocaine to non-toxic compounds is a promising way to prevent cocaine-induced toxicity. However, the short half-life of cocaine in the blood and the rapid conversion in the body to the hydrolysis-resistant metabolite benzoylecgonine, limits the therapeutic potential of serum proteins. Therefore, hydrolysis by tissue-specific hydrolases that do not generate benzoylecgonine deserves further investigation. Here, we report for the first time, the mechanism of cocaine hydrolysis by the human Carboxylesterase 2. We have combined conventional and accelerated Molecular Dynamics, which allowed us to identify the structural motions of the α1 and α10’ helices that act as a putative lid. Quantum Mechanics/Molecular Mechanics calculations on the full cycle showed that the rate-limiting step is the formation of benzoic acid (deacylation step) with an ΔG of 18.3 kcal.mol-1 (a value in close conformity with the experimental value of 19.7 kcal.mol-1).


2021 ◽  
Vol 22 (16) ◽  
pp. 8783
Author(s):  
Elżbieta U. Stolarczyk ◽  
Weronika Strzempek ◽  
Marta Łaszcz ◽  
Andrzej Leś ◽  
Elżbieta Menaszek ◽  
...  

Pharmacological and nutraceutical effects of isoflavones, which include genistein (GE), are attributed to their antioxidant activity protecting cells against carcinogenesis. The knowledge of the oxidation mechanisms of an active substance is crucial to determine its pharmacological properties. The aim of the present work was to explain complex oxidation processes that have been simulated during voltammetric experiments for our new thiolated genistein analog (TGE) that formed the self-assembled monolayer (SAM) on the gold electrode. The thiol linker assured a strong interaction of sulfur nucleophiles with the gold surface. The research comprised of the study of TGE oxidative properties, IR-ATR, and MALDI-TOF measurements of SAM before and after electrochemical oxidation. TGE has been shown to be electrochemically active. It undergoes one irreversible oxidation reaction and one quasi-reversible oxidation reaction in PBS buffer at pH 7.4.. The oxidation of TGE results in electroactive products composed likely from TGE conjugates (e.g., trimers) as part of polymer. The electroactive centers of TGE and its oxidation mechanism were discussed using IR supported by quantum chemical and molecular mechanics calculations. Preliminary in-vitro studies indicate that TGE exhibits higher cytotoxic activity towards DU145 human prostate cancer cells and is safer for normal prostate epithelial cells (PNT2) than genistein itself.


Applied Nano ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. 128-147
Author(s):  
Thomas Rybolt ◽  
Heir Jordan

On any size scale, it is important to know how strongly structural components are held together. The purpose of this work was to develop a means to estimate the collective binding energy holding together a bundle of aligned carbon nanotubes (CNTs). Carbon nanotubes in isolation and in bundles have unique and useful properties and applications within supramolecular structures and nanotechnology. Equations were derived to represent the total number of pairwise interactions between the CNTs found in various size and shape bundles. The shapes considered included diamond, hexagon, parallelogram, and rectangle. Parameters were used to characterize the size of a bundle for each defined shape. Force field molecular modeling was used to obtain the total bundle binding energies for a number of sample bundles. From the number of interactions per bundle, the binding energy per interaction was determined. This process was repeated for armchair CNTs having a range of length and circumference values. A simple equation described the interaction energy based on the length and circumference of the component armchair type nanotubes. When combined with the bundle shape and size parameters, the total bundle binding energy could be found. Comparison with whole bundle molecular mechanics calculations showed our formula-based approach to be effective.


2021 ◽  
Author(s):  
Vishwesh Venkatraman ◽  
Amitava Roy

Estimating entropy is crucial for understanding and modifying biological systems, such as protein-ligand binding. Current computational methods to estimate entropy require extensive, or at times prohibitively extensive, computational resources. This article presents SHAPE (SHape-based Accurate Predictor of Entropy), a new method that estimates the gas-phase entropy of small molecules purely from their surface geometry. Using SHAPE, the gas-phase entropy of small molecules can be computed in ~ 0.01 CPU hours with run time complexity of Ω(√(Na), where Na is the number of atoms. The accuracy of The method is within 1-2% of computationally expensive quantum mechanical or molecular mechanics calculations. We further show that the inclusion of gas-phase entropy, estimated using SHAPE, improves the rank-order correlation between binding affinity and the binding score from 0.18 to 0.40. The speed and accuracy of SHAPE make it well-suited for use in molecular docking studies as well as in the analysis of structure-activity relationships.


2021 ◽  
Vol 118 (21) ◽  
pp. e2101481118
Author(s):  
Takashi Nomura ◽  
Tetsunari Kimura ◽  
Yusuke Kanematsu ◽  
Daichi Yamada ◽  
Keitaro Yamashita ◽  
...  

Nitric oxide (NO) reductase from the fungus Fusarium oxysporum is a P450-type enzyme (P450nor) that catalyzes the reduction of NO to nitrous oxide (N2O) in the global nitrogen cycle. In this enzymatic reaction, the heme-bound NO is activated by the direct hydride transfer from NADH to generate a short-lived intermediate (I), a key state to promote N–N bond formation and N–O bond cleavage. This study applied time-resolved (TR) techniques in conjunction with photolabile-caged NO to gain direct experimental results for the characterization of the coordination and electronic structures of I. TR freeze-trap crystallography using an X-ray free electron laser (XFEL) reveals highly bent Fe–NO coordination in I, with an elongated Fe–NO bond length (Fe–NO = 1.91 Å, Fe–N–O = 138°) in the absence of NAD+. TR-infrared (IR) spectroscopy detects the formation of I with an N–O stretching frequency of 1,290 cm−1 upon hydride transfer from NADH to the Fe3+–NO enzyme via the dissociation of NAD+ from a transient state, with an N–O stretching of 1,330 cm−1 and a lifetime of ca. 16 ms. Quantum mechanics/molecular mechanics calculations, based on these crystallographic and IR spectroscopic results, demonstrate that the electronic structure of I is characterized by a singly protonated Fe3+–NHO•− radical. The current findings provide conclusive evidence for the N2O generation mechanism via a radical–radical coupling of the heme nitroxyl complex with the second NO molecule.


2021 ◽  
Vol 67 (3) ◽  
pp. 300-305
Author(s):  
A.M. Kulakova ◽  
M.G. Khrenova ◽  
A.V. Nemukhin

Human carboxylesterases are involved in the protective processes of detoxification during the hydrolytic metabolism of xenobiotics. Knowledge of the molecular mechanisms of substrates hydrolysis in the enzymes active site is necessary for the rational drug design. In this work, the molecular mechanism of the hydrolysis reaction of para-nitrophenyl acetate in the active site of human carboxylesterase was determined using modern methods of molecular modeling. According to the combined method of quantum mechanics/molecular mechanics calculations, the chemical reaction occurs within four elementary steps, including two steps of the acylation stage, and two steps of the deacylation stage. All elementary steps have low energy barriers, with the gradual lowering of the intermediate energies that stimulates reaction in the forward direction. The molecular docking was used to estimate the binding constants of the enzyme-substrate complex and the dissociation constant of enzyme-product complexes. The effective kinetic parameters of the enzymatic hydrolysis in the active site of carboxylesterase are determined by numerical solution of the differential kinetic equations.


Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4544 ◽  
Author(s):  
Manuela Stefanelli ◽  
Federica Mandoj ◽  
Gabriele Magna ◽  
Raffaella Lettieri ◽  
Mariano Venanzi ◽  
...  

An overview of the solvent-driven aggregation of a series of chiral porphyrin derivatives studied by optical methods (UV/Vis, fluorescence, CD and RLS spectroscopies) is herein reported. The investigated porphyrins are characterized by the presence in the meso-positions of glycol-, steroidal- and glucosteroidal moieties, conferring amphiphilicity and solubility in aqueous media to the primarily hydrophobic porphyrin platform. Aggregation of the macrocycles is driven by a change in bulk solvent composition, forming architectures with supramolecular chirality, steered by the stereogenic centers on the porphyrin peripheral positions. The aggregation behavior and chiroptical properties of the final aggregated species strongly depend on the number and stereogenicity of the ancillary groups that dictate the mutual spatial arrangement of the porphyrin chromophores and their further organization in larger structures, usually detectable by different microscopies, such as AFM and SEM. Kinetic studies are fundamental to understand the aggregation mechanism, which is frequently found to be dependent on the substrate concentration. Additionally, Molecular Mechanics calculations can give insights into the intimate nature of the driving forces governing the self-assembly process. The critical use of these combined methods can shed light on the overall self-assembly process of chirally-functionalized macrocycles, with important implications on the development of chiral porphyrin-based materials.


Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4264
Author(s):  
Silvio Osella ◽  
Markéta Paloncýová ◽  
Maryam Sahi ◽  
Stefan Knippenberg

The fluorescent molecule diphenylhexatriene (DPH) has been often used in combination with fluorescence anisotropy measurements, yet little is known regarding the non-linear optical properties. In the current work, we focus on them and extend the application to fluorescence, while paying attention to the conformational versatility of DPH when it is embedded in different membrane phases. Extensive hybrid quantum mechanics/molecular mechanics calculations were performed to investigate the influence of the phase- and temperature-dependent lipid environment on the probe. Already, the transition dipole moments and one-photon absorption spectra obtained in the liquid ordered mixture of sphingomyelin (SM)-cholesterol (Chol) (2:1) differ largely from the ones calculated in the liquid disordered DOPC and solid gel DPPC membranes. Throughout the work, the molecular conformation in SM:Chol is found to differ from the other environments. The two-photon absorption spectra and the ones obtained by hyper-Rayleigh scattering depend strongly on the environment. Finally, a stringent comparison of the fluorescence anisotropy decay and the fluorescence lifetime confirm the use of DPH to gain information upon the surrounding lipids and lipid phases. DPH might thus open the possibility to detect and analyze different biological environments based on its absorption and emission properties.


Chemosensors ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 48
Author(s):  
Hiroshi Ikeda

Chemosensors have attracted considerable attention among the numerous strategies for detecting organic molecules in water. A turn-off mechanism was previously employed for the construction of a cyclodextrin (CD) chemosensor. This mechanism is greatly effective but has several shortcomings. In order to overcome these shortcomings, new fluorescent chemosensors NC0αCD, NC0βCD, and NC0γCD, which were (7-nitrobenz-2-oxa-1,3-diazol-4-yl)amine-modified α-CD, β-CD, and γ-CD, respectively, were prepared. Their guest selectivities were different from those of previously reported CD chemosensors. Here, the mechanism of new CD chemosensors was investigated using nuclear magnetic resonance (NMR) spectroscopy and molecular mechanics calculations. The fluorescence intensity of NC0βCD and NC0γCD slightly decreased and largely increased, respectively, upon the addition of ursodeoxycholic acid as a guest. This is due to the fact that the fluorophore of NC0βCD moved away to the hydrophilic bulk water to form hydrogen bonds between the host and the guest, while the fluorophore of NC0γCD remained located at the primary hydroxy side of the γ-CD unit to form a stable inclusion complex with hydrogen bonds between the fluorophore and the guest. NC0αCD also acted as a turn-on chemosensor for small guests, which could not be detected by the previous CD chemosensors. The motion restriction of the fluorophore through the generation of inclusion complexes could also contribute to increase in fluorescence intensity.


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