QM/MM method
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Hybrid QM/MM methods combine the rigor of quantum mechanical (QM) calculations with the low computational cost of empirical molecular mechanical (MM) treatment allowing to capture dynamic properties to probe critical atomistic details of enzyme reactions. Catalysis by RNA enzymes (ribozymes) has only recently begun to be addressed with QM/MM approaches and is thus still a field under development. This review surveys methodology as well as recent advances in QM/MM applications to RNA mechanisms, including those of the HDV, hairpin, and hammerhead ribozymes, as well as the ribosome. We compare and correlate QM/MM results with those from QM and/or molecular dynamics (MD) simulations, and discuss scope and limitations with a critical eye on current shortcomings in available methodologies and computer resources. We thus hope to foster mutual appreciation and facilitate collaboration between experimentalists and theorists to jointly advance our understanding of RNA catalysis at an atomistic level.
- MeSH
- biofyzika metody MeSH
- fosfáty chemie MeSH
- fosforylace MeSH
- hořčík chemie MeSH
- katalýza MeSH
- konformace nukleové kyseliny MeSH
- kvantová teorie MeSH
- lidé MeSH
- molekulární modely MeSH
- počítačová simulace MeSH
- ribozomy chemie MeSH
- RNA katalytická chemie MeSH
- RNA virová chemie MeSH
- RNA chemie MeSH
- software MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
One of the most common methods to treat the electrostatic effect of the environment in QM/MM calculations is to include the MM atoms as point charges in the QM Hamiltonian. In this case, a microiterative geometry optimization ignoring the QM contributions to the forces in the relaxation of the environment cannot yield exact stationary points. One solution that has been suggested in the literature is based on using a constant additive correction to the MM gradient during the microiterations, determined in the preceding macroiteration. Here, we analyze the convergence properties of the gradient correction method and point out that a smooth relaxation is not ensured if the curvature of the approximate, MM-based description of the potential energy surface of the environment is too small in comparison with the exact one. We suggest a computationally cheap second-order correction that uses an estimated Hessian from the Davidon-Fletcher-Powell method to tackle the problems caused by the too small curvature. Test calculations on four metalloenzymatic systems (∼100 QM atoms, ∼2000 relaxed MM atoms, ∼20,000 atoms in total) show that our approach efficiently restores the convergence where gradient correction alone would lead to oscillations.
- MeSH
- kvantová teorie MeSH
- simulace molekulární dynamiky MeSH
- software MeSH
- výpočetní biologie metody MeSH
- Publikační typ
- časopisecké články MeSH
Mechanistic studies on the hydrolytic dehalogenation catalyzed by haloalkane dehalogenases are of importance for environmental and industrial applications. Here, Car-Parrinello (CP) and ONIOM hybrid quantum-mechanical/molecular mechanics (QM/MM) are used investigate the second reaction step of the catalytic cycle, which comprises a general base-catalyzed hydrolysis of an ester intermediate (EI) to alcohol and free enzyme. We focus on the enzyme LinB from Sphingomonas paucimobilis UT26, for which the X-ray structure at atomic resolution is available. In agreement with previous proposals, our calculations suggest that a histidine residue (His272), polarized by glutamate (Glu132), acts as a base, accepting a proton from the catalytic water molecule and transferring it to an alcoholate ion. The reaction proceeds through a metastable tetrahedral intermediate, which shows an easily reversed reaction to the EI. In the formation of the products, the protonated aspartic acid (Asp108) can easily adopt conformation of the relaxed state found in the free enzyme. The overall free energy barrier of the reaction calculated by potential of the mean force integration using CP-QM/MM calculations is equal to 19.5 +/- 2 kcal . mol(-1). The lowering of the energy barrier of catalyzed reaction with respect to the water reaction is caused by strong stabilization of the reaction intermediate and transition state and their preorganization by electrostatic field of the enzyme. (c) 2007 Wiley-Liss, Inc.
- MeSH
- bakteriální proteiny chemie metabolismus MeSH
- financování organizované MeSH
- halogenace MeSH
- hydrolasy chemie metabolismus MeSH
- hydrolýza MeSH
- katalýza MeSH
- kinetika MeSH
- konformace proteinů MeSH
- kvantová teorie MeSH
- molekulární modely MeSH
- Sphingomonas enzymologie metabolismus MeSH
- termodynamika MeSH
- vazebná místa MeSH
Ru(II) "piano-stool" complexes belong to group of biologically active metallocomplexes with promising anticancer activity. In this study, we investigate the reaction mechanism of [(η(6)-benzene)Ru(II)(en)(H(2)O)](2+) (en = ethylenediamine) complex binding to DNA by hybrid QM/MM computational techniques. The reaction when the Ru(II) complex is coordinated on N7-guanine from major groove is explored. Two reaction pathways, direct binding to N7 position and two-step mechanism passing through O6 position, are considered. It was found that the reaction is exothermic and the direct binding process is preferred kinetically. In analogy to cisplatin, we also explored the possibility of intrastrand cross-link formation where the Ru(II) complex makes a bridge between two adjacent guanines. Two different pathways were found, leading to a final structure with released benzene ligand. This process is exothermic; however, one pathway is blocked by relatively high initial activation barrier. Geometries, energies, and electronic properties analyzed by atoms in molecules and natural population analysis methods are discussed.
The glycosylation of cell surface proteins plays a crucial role in a multitude of biological processes, such as cell adhesion and recognition. To understand the process of protein glycosylation, the reaction mechanisms of the participating enzymes need to be known. However, the reaction mechanism of retaining glycosyltransferases has not yet been sufficiently explained. Here we investigated the catalytic mechanism of human isoform 2 of the retaining glycosyltransferase polypeptide UDP-GalNAc transferase by coupling two different QM/MM-based approaches, namely a potential energy surface scan in two distance difference dimensions and a minimum energy reaction path optimisation using the Nudged Elastic Band method. Potential energy scan studies often suffer from inadequate sampling of reactive processes due to a predefined scan coordinate system. At the same time, path optimisation methods enable the sampling of a virtually unlimited number of dimensions, but their results cannot be unambiguously interpreted without knowledge of the potential energy surface. By combining these methods, we have been able to eliminate the most significant sources of potential errors inherent to each of these approaches. The structural model is based on the crystal structure of human isoform 2. In the QM/MM method, the QM region consists of 275 atoms, the remaining 5776 atoms were in the MM region. We found that ppGalNAcT2 catalyzes a same-face nucleophilic substitution with internal return (SNi). The optimized transition state for the reaction is 13.8 kcal/mol higher in energy than the reactant while the energy of the product complex is 6.7 kcal/mol lower. During the process of nucleophilic attack, a proton is synchronously transferred to the leaving phosphate. The presence of a short-lived metastable oxocarbenium intermediate is likely, as indicated by the reaction energy profiles obtained using high-level density functionals.
- MeSH
- algoritmy MeSH
- chemické modely * MeSH
- glykosylace MeSH
- glykosyltransferasy chemie ultrastruktura MeSH
- katalýza MeSH
- kinetika MeSH
- konformace proteinů MeSH
- molekulární modely * MeSH
- počítačová simulace MeSH
- polysacharidy chemie ultrastruktura MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Organophosphorus compounds (OP) nerve agents are among the most toxic chemical substances known. Their toxicity is due to their ability to bind to acetylcholinesterase. Currently, some enzymes, such as phosphotriesterase, human serum paraoxonase 1 and diisopropyl fluorophosphatase, capable of degrading OP, have been characterized. Regarding the importance of bioremediation methods for detoxication of OP, this work aims to study the interaction modes between the human human deoxyuridine triphosphate nucleotidohydrolase (dUTPase) and Sarin and VX, considering their Rp and Sp enantiomers, to evaluate the asymmetric catalysis of those compounds. In previous work, this enzyme has shown good potential to degrade phosphotriesters, and based on this characteristic, we have applied the human dUTPase to the OP degradation. Molecular docking, chemometrics and mixed quantum and molecular mechanics calculations have been employed, showing a good interaction between dUTPase and OP. Two possible reaction mechanisms were tested, and according to our theoretical results, the catalytic degradation of OP by dUTPase can take place via both mechanisms, beyond being stereoselective, that is, dUTPase cleaves one enantiomer preferentially in relation to other. Chemometric techniques provided excellent assistance for performing this theoretical investigation. The dUTPase study shows importance by the fact of it being a human enzyme. Communicated by Ramaswamy H. Sarma.
- MeSH
- analýza hlavních komponent MeSH
- biodegradace MeSH
- katalytická doména MeSH
- kvantová teorie * MeSH
- lidé MeSH
- nervová bojová látka chemie metabolismus MeSH
- organofosforové sloučeniny chemie metabolismus MeSH
- organothiofosforové sloučeniny chemie metabolismus MeSH
- pyrofosfatasy metabolismus MeSH
- sarin chemie metabolismus MeSH
- simulace molekulového dockingu * MeSH
- vodíková vazba MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
A semiempirical quantum mechanical PM6-DH2 method accurately covering the dispersion interaction and H-bonding was used to score fifteen structurally diverse CDK2 inhibitors. The geometries of all the complexes were taken from the X-ray structures and were reoptimised by the PM6-DH2 method in continuum water. The total scoring function was constructed as an estimate of the binding free energy, i.e., as a sum of the interaction enthalpy, interaction entropy and the corrections for the inhibitor desolvation and deformation energies. The applied scoring function contains a clear thermodynamical terms and does not involve any adjustable empirical parameter. The best correlations with the experimental inhibition constants (ln K (i)) were found for bare interaction enthalpy (r (2) = 0.87) and interaction enthalpy corrected for ligand desolvation and deformation energies (r (2) = 0.77); when the entropic term was considered, however, the correlation becomes worse but still acceptable (r (2) = 0.52). The resulting correlation based on the PM6-DH2 scoring function is better than previously published function based on various docking/scoring, SAR studies or advanced QM/MM approach, however, the robustness is limited by number of available experimental data used in the correlation. Since a very similar correlation between the experimental and theoretical results was found also for a different system of the HIV-1 protease, the suggested scoring function based on the PM6-DH2 method seems to be applicable in drug design, even if diverse protein-ligand complexes have to be ranked.
- MeSH
- cyklin-dependentní kinasa 2 antagonisté a inhibitory metabolismus MeSH
- inhibitory proteinkinas chemie farmakologie MeSH
- kvantová teorie MeSH
- lidé MeSH
- ligandy MeSH
- molekulární modely MeSH
- racionální návrh léčiv MeSH
- termodynamika MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
t is known that nerve agents are potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of the neurotransmitter acetylcholine and, thus, transmission of nerve impulses. The process of AChE inhibition by nerve agents can be reversed by a nucleophile able to dephosphorylate the enzyme. In this sense, oximes exhibit this characteristic and are able to remove the neurotoxic and reactivate AChE. Here, we review experimental and theoretical results involving docking and quantum mechanical-molecular mechanics hybrid methods (QM/MM), using Molegro® and Spartan® softwares to analyze the interaction of different nerve agents and oximes with AChE and to evaluate kinetic constants of reactivation.
- Klíčová slova
- QM/MM,
- MeSH
- acetylcholinesterasa * farmakologie účinky léků MeSH
- chemická válka MeSH
- krysa rodu rattus MeSH
- molekulární modely * MeSH
- myši MeSH
- neurotoxiny antagonisté a inhibitory škodlivé účinky MeSH
- organofosfáty * farmakologie škodlivé účinky MeSH
- oximy * farmakologie terapeutické užití MeSH
- simulace molekulového dockingu MeSH
- techniky in vitro MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- hodnotící studie MeSH
- práce podpořená grantem MeSH
In this review primarily written for non-experts we explain basic methodological aspects and interpretation of modern quantum chemical (QM) computations applied to nucleic acids. We introduce current reference QM computations on small model systems consisting of dozens of atoms. Then we comment on recent advance of fast and accurate dispersion-corrected density functional theory methods, which will allow computations of small but complete nucleic acids building blocks in the near future. The qualitative difference between QM and molecular mechanics (MM, force field) computations is discussed. We also explain relation of QM and molecular simulation computations to experiments.
