Molecular dynamics simulation in aqueous solution of N -methylazetidinone as a model of β -lactam antibiotics (original) (raw)
Related papers
The Journal of Physical Chemistry B, 1997
In this work we present a theoretical study of neutral and alkaline hydrolyses of N-methylazetidinone as a model of biological hydrolysis of -lactam antibiotics. Calculations have been carried out at the HF and MP2 levels using the 3-21G, 6-31G*, and 6-31+G* basis sets. Solvent effects have been included by means of a polarizable continuum model. Our results indicate two possible reaction mechanisms for the -lactam hydrolysis: concerted and stepwise. In both the neutral and alkaline hydrolyses the concerted mechanism presents a free energy barrier lower than that of the stepwise mechanism.
Journal of Computational Chemistry, 1992
We used semi-empirical and ab initio calculations to investigate the nucleophilic attack of the OHion on the 8-lactam carbonyl group. Both allowed us to detect reaction intermediates pertaining to proton-transfer reactions rather than the studied reaction. We also used the PM3 semi-empirical method to investigate the influence of the solvent on the process. The AMSOL method predicts the occurrence of a potential barrier of 20.7 kcal/mol due to the desolvation of the OHion in approaching theb-lactam carbonyl group. Using the supermolecular approach and a H,O solvation sphere of 20 molecules around the solute, the potential barrier is lowered to 17.5 kcal/mol, which is very close to the experimental value (16.7 kcal/mol).
Helvetica Chimica Acta, 1996
We used semi-empirical and ab initio calculations to investigate the nucleophilic attack of the OHion on the 8-lactam carbonyl group. Both allowed us to detect reaction intermediates pertaining to proton-transfer reactions rather than the studied reaction. We also used the PM3 semi-empirical method to investigate the influence of the solvent on the process. The AMSOL method predicts the occurrence of a potential barrier of 20.7 kcal/mol due to the desolvation of the OHion in approaching theb-lactam carbonyl group. Using the supermolecular approach and a H,O solvation sphere of 20 molecules around the solute, the potential barrier is lowered to 17.5 kcal/mol, which is very close to the experimental value (16.7 kcal/mol).
ChemInform, 1996
We used semi-empirical and ab initio calculations to investigate the nucleophilic attack of the OHion on the 8-lactam carbonyl group. Both allowed us to detect reaction intermediates pertaining to proton-transfer reactions rather than the studied reaction. We also used the PM3 semi-empirical method to investigate the influence of the solvent on the process. The AMSOL method predicts the occurrence of a potential barrier of 20.7 kcal/mol due to the desolvation of the OHion in approaching theb-lactam carbonyl group. Using the supermolecular approach and a H,O solvation sphere of 20 molecules around the solute, the potential barrier is lowered to 17.5 kcal/mol, which is very close to the experimental value (16.7 kcal/mol).
Theoretical studies of the hydrolysis of antibiotics catalyzed by a metallo-β-lactamase
Archives of Biochemistry and Biophysics, 2015
In this paper, hybrid QM/MM molecular dynamics (MD) simulations have been performed to explore the mechanisms of hydrolysis of two antibiotics, Imipenen (IMI), an antibiotic belonging to the subgroup of carbapenems, and the Cefotaxime (CEF), a third-generation cephalosporin antibiotic, in the active site of a mono-nuclear βlactamase, CphA from Aeromonas hydrophila. According to our results, significant different transition state structures are obtained for the hydrolysis of both antibiotics: while the TS of the CEF is a ionic species with negative charge on nitrogen, the IMI TS presents a tetrahedral-like character with negative charge on oxygen atom of the carbonyl group of the lactam ring. Thus, dramatic conformational changes can take place in the cavity of CphA to accommodate different substrates, which would be the origin of its substrate promiscuity. This feature of the β-lactamase would be in turn, associated to the different mechanisms that the protein employs to hydrolyze the different antibiotics; i.e. the catalytic promiscuity. Since CphA shows only activity against carbapenem antibiotic, this study will be used to shed some light into the origin of the selectivity of the different MbL and, as a consequence, into the discovery of specific and potent MβL inhibitors against a broad spectrum of bacterial pathogens.
A study of the nucleophilic attack of the beta-lactamic bond of antibiotics in water solution
Journal of Molecular Structure: THEOCHEM, 2001
The nucleophilic attack of a series of 19 b-lactamic antibiotics (13 penicillins and six cephalosporins), as well as that of the clavulanic acid (CLA), by a hydroxylic anion, is considered in water solution and in gas phase. It is found that the tetrahedral intermediate formation does not occur spontaneously anymore in water solution, but the reaction has to overpass an energy barrier due to the desolvation of the reactants. The desolvation energy barriers, as well as the tetrahedral complex formation energy in water solution are calculated into the PM3 semi-empirical approach and the supermolecule model. In the same way, the energy barriers for the b-lactamic bond breaking and the ®nal product formation energies are determined. The results are compared with those obtained previously for the same molecules in the gas phase.
Structure, Thermodynamics and Energetics of Drug-DNA Interactions: Computer Modeling and Experiment
Application of Computational Techniques in Pharmacy and Medicine, 2014
In this chapter we demonstrate the large usefulness of using complex approach for understanding the mechanism of binding of biologically active compounds (antitumour antibiotics, mutagens etc.) with nucleic acids (NA). The applications of various biophysical methods and computer modeling to determination of structural (Infra-red and Raman vibrational spectroscopies, computer modeling by means of Monte-Carlo, molecular docking and molecular dynamics methods) and thermodynamic (UV-VIS spectrophotometry, microcalorimetry, molecular dynamics simulation) parameters of NA-ligand complexation with estimation of the role of water environment in this process, are discussed. The strategy of energy analysis of the NA-ligand binding reactions in solution is described, which is based on decomposition of experimentally measured net Gibbs free energy of binding in terms of separate energetic contributions from particular physical factors. The main outcome of such analysis is to answer the questions "What physical factors and to what extent stabilize/destabilize NA-ligand complexes?" and "What physical factors most strongly affect the bioreceptor binding affinity?"
Theoretical Study of the Alkaline Hydrolysis of a Bicyclic Aza-β-lactam
The Journal of Physical Chemistry B, 2000
Solvent effects were considered via IPCM (isodensity polarizable continuum model) calculations at the IPCM/6-31+G*//RHF/6-31+G* level. The alkaline hydrolysis of-lactams begins with a nucleophilic attack of the hydroxyl ion on the carbonyl of the-lactam ring. The tetrahedral intermediate thus formed undergoes cleavage of the C 7-N 4 bond to give the reaction end products. In addition to the typical cleavage reaction, the-lactam studied can undergo opening at the C 7-N 6 bond (Scheme 1). Both processes have a similar activation energy that varies slightly depending on the particular computation method used. The most stable end products are those formed via the typical mechanism. In any case, both mechanisms yield products possessing a carbamate group, which suggests that the starting aza-lactam might be an effective inhibitor for-lactamases.
Helvetica Chimica Acta, 1994
We used semi-empirical and ab initio calculations to investigate the nucleophilic attack of the OHion on the 8-lactam carbonyl group. Both allowed us to detect reaction intermediates pertaining to proton-transfer reactions rather than the studied reaction. We also used the PM3 semi-empirical method to investigate the influence of the solvent on the process. The AMSOL method predicts the occurrence of a potential barrier of 20.7 kcal/mol due to the desolvation of the OHion in approaching theb-lactam carbonyl group. Using the supermolecular approach and a H,O solvation sphere of 20 molecules around the solute, the potential barrier is lowered to 17.5 kcal/mol, which is very close to the experimental value (16.7 kcal/mol).
Journal of Physical Chemistry B, 2020
Glucosamine is a component of many cellular glycoproteins that constitutes the cartilage, and it has several biological activities, such as anti-inflammatory, arthritis treatment, antioxidant, antifibrotic, anticancer, and dermatological treatment. Considering that the biological activities of glucosamine occur mainly in an aqueous environment, it is essential to understand the effects of aqueous solvent on its geometric and electronic parameters using ab initio molecular dynamics. The Car-Parrinello molecular dynamics results show that the hydroxyl groups form stable hydrogen bonds with the water molecules with intensities ranging from weak (closed-shell interaction) to intermediate (partially covalent interactions). The H-bond formed between the amino group and the water molecule range from weak (closed-shell) to strong (covalent), and it shows an infinity residence time. The natural bonding orbitals (NBO) approach was applied to analyze the effects of charge-transfer interactions on the behavior of the hydrogen bonds. The main contribution to stabilizing energies comes from n → σ* hyperconjugation and explains the stability of the H-bonds. The energy barrier for the proton transfer from water to the amino group is 0.88 kcal/mol, and the van der Waals complex energy is 0.3 kcal/mol. The low protonation energy barrier shows that glucosamine can be protonated in an aqueous environment at room temperature, which helps to explain many of its biological activities.