Current possibilities and limitations of the simulation of in vivo magnetic resonance spectroscopic signals are demonstrated from the point of view of a simulation software user as well as its programmer. A brief review of the quantum-mechanical background addresses the specific needs of simulation implementation and in vivo MR spectroscopy in general. Practical application examples demonstrate how flexible simulation software, such as NMRScopeB, can be utilized not only for the preparation of metabolite basis signals for quantification of metabolite concentrations, but also in pulse sequence development, assessment of artifacts and analyzing mechanism leading to unexpected signal phenomena.

• Klíčová slova
• In vivo spectroscopy, Magnetic resonance spectroscopy, Metabolite concentration quantitation, Quantum mechanical simulation,
• MeSH
• biologické modely MeSH
• kvantová teorie * MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie metody   MeSH
• magnetická rezonanční tomografie metody   MeSH
• počítačová simulace MeSH
• software * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

We combined atomistic molecular-dynamics simulations with quantum-mechanical calculations to investigate the sequence dependence of the stretching behavior of duplex DNA. Our combined quantum-mechanical/molecular-mechanical approach demonstrates that molecular-mechanical force fields are able to describe both the backbone and base-base interactions within the highly distorted nucleic acid structures produced by stretching the DNA from the 5' ends, which include conformations containing disassociated basepairs, just as well as these force fields describe relaxed DNA conformations. The molecular-dynamics simulations indicate that the force-induced melting pathway is sequence-dependent and is influenced by the availability of noncanonical hydrogen-bond interactions that can assist the disassociation of the DNA basepairs. The biological implications of these results are discussed.

• MeSH
• chemické modely * MeSH
• DNA chemie   ultrastruktura   MeSH
• kinetika MeSH
• konformace nukleové kyseliny MeSH
• kvantová teorie MeSH
• mechanický stres MeSH
• modul pružnosti MeSH
• molekulární modely * MeSH
• počítačová simulace MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA MeSH

Practical challenges in simulating quantum systems on classical computers have been widely recognized in the quantum physics and quantum chemistry communities over the past century. Although many approximation methods have been introduced, the complexity of quantum mechanics remains hard to appease. The advent of quantum computation brings new pathways to navigate this challenging and complex landscape. By manipulating quantum states of matter and taking advantage of their unique features such as superposition and entanglement, quantum computers promise to efficiently deliver accurate results for many important problems in quantum chemistry, such as the electronic structure of molecules. In the past two decades, significant advances have been made in developing algorithms and physical hardware for quantum computing, heralding a revolution in simulation of quantum systems. This Review provides an overview of the algorithms and results that are relevant for quantum chemistry. The intended audience is both quantum chemists who seek to learn more about quantum computing and quantum computing researchers who would like to explore applications in quantum chemistry.

• MeSH
• algoritmy MeSH
• chemické modely * MeSH
• kvantová teorie * MeSH
• počítačové metodologie MeSH
• simulace molekulární dynamiky MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH

Knowledge of geometrical and physico-chemical properties of the sugar-phosphate backbone substantially contributes to the comprehension of the structural dynamics, function and evolution of nucleic acids. We provide a side by side overview of structural biology/bioinformatics, quantum chemical and molecular mechanical/simulation studies of the nucleic acids backbone. We highlight main features, advantages and limitations of these techniques, with a special emphasis given to their synergy. The present status of the research is then illustrated by selected examples which include classification of DNA and RNA backbone families, benchmark structure-energy quantum chemical calculations, parameterization of the dihedral space of simulation force fields, incorporation of arsenate into DNA, sugar-phosphate backbone self-cleavage in small RNA enzymes, and intricate geometries of the backbone in recurrent RNA building blocks. Although not apparent from the current literature showing limited overlaps between the QM, simulation and bioinformatics studies of the nucleic acids backbone, there in fact should be a major cooperative interaction between these three approaches in studies of the sugar-phosphate backbone.

• MeSH
• DNA chemie   MeSH
• fosfáty chemie   MeSH
• kvantová teorie * MeSH
• molekulární struktura MeSH
• RNA chemie   MeSH
• sacharidy chemie   MeSH
• simulace molekulární dynamiky * MeSH
• výpočetní biologie MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• DNA MeSH
• fosfáty MeSH
• RNA MeSH
• sacharidy MeSH

The use of quantum mechanical potentials in protein-ligand affinity prediction is becoming increasingly feasible with growing computational power. To move forward, validation of such potentials on real-world challenges is necessary. To this end, we have collated an extensive set of over a thousand galectin inhibitors with known affinities and docked them into galectin-3. The docked poses were then used to systematically evaluate several modern force fields and semiempirical quantum mechanical (SQM) methods up to the tight-binding level under consistent computational workflow. Implicit solvation models available with the tested methods were used to simulate solvation effects. Overall, the best methods in this study achieved a Pearson correlation of 0.7-0.8 between the computed and experimental affinities. There were differences between the tested methods in their ability to rank ligands across the entire ligand set as well as within subsets of structurally similar ligands. A major discrepancy was observed for a subset of ligands that bind to the protein via a halogen bond, which was clearly challenging for all the tested methods. The inclusion of an entropic term calculated by the rigid-rotor-harmonic-oscillator approximation at SQM level slightly worsened correlation with experiment but brought the calculated affinities closer to experimental values. We also found that the success of the prediction strongly depended on the solvation model. Furthermore, we provide an in-depth analysis of the individual energy terms and their effect on the overall prediction accuracy.

• MeSH
• galektiny * chemie   metabolismus   MeSH
• konformace proteinů MeSH
• kvantová teorie * MeSH
• ligandy MeSH
• simulace molekulového dockingu MeSH
• termodynamika MeSH
• vazba proteinů MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• galektiny * MeSH
• ligandy MeSH

Manganese superoxide dismutases (MnSODs) are enzymes that convert two molecules of the poisonous superoxide radical into molecular oxygen and hydrogen peroxide. During the reaction, the manganese ion cycles between the Mn(2+) and Mn(3+) oxidation states and accomplishes its enzymatic action in two half-cycles (corresponding to the oxidation and reduction of O(2)(-)). Despite many experimental and theoretical studies dealing with SODs, including quantum chemical active-site-model studies of numerous variants of the reaction mechanisms, several details of MnSOD enzymatic action are still unclear. In this study, we have modeled and compared four reaction pathways (one associative, one dissociative, and two second-sphere) in a protein environment using the QM/MM approach (combined quantum and molecular mechanics calculations) at the density functional theory level. The results were complemented by CASSCF/CASPT2/MM single-point energy calculations for the most plausible models to account properly for the multireference character of the various spin multiplets. The results indicate that the oxidation of O(2)(-) to O(2) most likely occurs by an associative mechanism following a two-state (quartet-octet) reaction profile. The barrier height is estimated to be less than 25 kJ.mol(-1). On the other hand, the conversion of O(2)(-) to H(2)O(2) is likely to take place by a second-sphere mechanism, that is, without direct coordination of the superoxide radical to the manganese center. The reaction pathway involves the conical intersection of two quintet states, giving rise to an activation barrier of approximately 60 kJ.mol(-1). The calculations also indicate that the associative mechanism can represent a competitive pathway in the second half-reaction with the overall activation barrier being only slightly higher than the activation barrier in the second-sphere mechanism. The activation barriers along the proposed reaction pathways are in very good agreement with the experimentally observed reaction rates of SODs (k(cat) approximately 10(4)-10(5) s(-1)).

• MeSH
• chemické modely * MeSH
• elektrony MeSH
• kvantová teorie * MeSH
• počítačová simulace * MeSH
• superoxiddismutasa chemie   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• superoxiddismutasa MeSH

In the present work, we performed a complementary quantum mechanical (QM) study to describe the mechanism by which deprotonated pralidoxime (2-PAM) could reactivate human (Homo sapiens sapiens) acetylcholinesterase (HssAChE) inhibited by the nerve agent VX. Such a reaction is proposed to occur in subsequent addition-elimination steps, starting with a nucleophile bimolecular substitution (SN2) mechanism through the formation of a trigonal bipyramidal transition state (TS). A near attack conformation (NAC), obtained in a former study using molecular mechanics (MM) calculations, was taken as a starting point for this project, where we described the possible formation of the TS. Together, this combined QM/MM study on AChE reactivation shows the feasibility of the reactivation occurring via attack of the deprotonated form of 2-PAM against the Ser203-VX adduct of HssAChE.

• Klíčová slova
• 2-PAM, QM/MM method, VX, acetylcholinesterase,
• MeSH
• acetylcholinesterasa chemie   účinky léků   MeSH
• katalytická doména MeSH
• kvantová teorie MeSH
• lidé MeSH
• molekulární konformace MeSH
• organothiofosforové sloučeniny farmakologie   MeSH
• pralidoximové sloučeniny chemie   farmakologie   MeSH
• protony MeSH
• serin chemie   MeSH
• simulace molekulární dynamiky MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• organothiofosforové sloučeniny MeSH
• pralidoxime MeSH Prohlížeč
• pralidoximové sloučeniny MeSH
• protony MeSH
• serin MeSH
• VX MeSH Prohlížeč

We present comprehensive testing of solvent representation in quantum mechanics (QM)-based scoring of protein-ligand affinities. To this aim, we prepared 21 new inhibitors of cyclin-dependent kinase 2 (CDK2) with the pyrazolo[1,5-a]pyrimidine core, whose activities spanned three orders of magnitude. The crystal structure of a potent inhibitor bound to the active CDK2/cyclin A complex revealed that the biphenyl substituent at position 5 of the pyrazolo[1,5-a]pyrimidine scaffold was located in a previously unexplored pocket and that six water molecules resided in the active site. Using molecular dynamics, protein-ligand interactions and active-site water H-bond networks as well as thermodynamics were probed. Thereafter, all the inhibitors were scored by the QM approach utilizing the COSMO implicit solvent model. Such a standard treatment failed to produce a correlation with the experiment (R2 = 0.49). However, the addition of the active-site waters resulted in significant improvement (R2 = 0.68). The activities of the compounds could thus be interpreted by taking into account their specific noncovalent interactions with CDK2 and the active-site waters. In summary, using a combination of several experimental and theoretical approaches we demonstrate that the inclusion of explicit solvent effects enhance QM/COSMO scoring to produce a reliable structure-activity relationship with physical insights. More generally, this approach is envisioned to contribute to increased accuracy of the computational design of novel inhibitors.

• Klíčová slova
• ATP-competitive type I inhibitors, Cyclin-dependent kinase 2, Molecular dynamics, Protein-ligand binding, Pyrazolo[1,5-a]pyrimidine, Quantum mechanical scoring, Water thermodynamics, X-ray crystal structure,
• MeSH
• cyklin A metabolismus   MeSH
• cyklin-dependentní kinasa 2 antagonisté a inhibitory   chemie   metabolismus   MeSH
• inhibitory proteinkinas chemie   metabolismus   farmakologie   MeSH
• katalytická doména * MeSH
• kvantová teorie * MeSH
• lidé MeSH
• pyrimidiny chemie   metabolismus   farmakologie   MeSH
• racionální návrh léčiv MeSH
• rozpouštědla chemie   MeSH
• simulace molekulární dynamiky MeSH
• voda chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cyklin A MeSH
• cyklin-dependentní kinasa 2 MeSH
• inhibitory proteinkinas MeSH
• pyrimidiny MeSH
• rozpouštědla MeSH
• voda MeSH

A quantum mechanics (QM)-based scoring function has been applied to complexes of cyclin-dependent kinase 2 (CDK2) and thirty-one pyrazolo[1,5-a]pyrimidine-based inhibitors and their bioisosteres. A hybrid three-layer QM/MM setup (DFT-D/PM6-D3H4X/AMBER in generalized Born solvent) was used here for the first time as an extension of our previous full QM and SQM/MM (SQM means semiempirical QM) approaches. Two approaches to obtain the structures of the CDK2/inhibitor complexes were examined: i) building the modifications from one X-ray structure available coupled with a conformational search and ii) docking the compounds into CDK2. The QM-based scoring entailed a QM/SQM/MM optimization followed by calculations of the binding scores which were subsequently correlated with the experimental binding free energies. The correlation for the building protocol was good (r(2) = 0.64, predictive index = 0.81), whereas the docking approach failed. A decomposition of the interaction energies to ligand fragments enabled us to rationalize the differences in the binding affinities. In conclusion, we have developed and refined a QM-based scoring protocol and successfully applied it to reproduce the binding affinities in congeneric series of CDK2 inhibitors and to rationalize their potency. We thus propose that such a tool can be used in computer-aided rational drug design.

• MeSH
• cyklin-dependentní kinasa 2 antagonisté a inhibitory   chemie   metabolismus   MeSH
• kvantová teorie MeSH
• lidé MeSH
• pyrazoly chemie   farmakologie   MeSH
• pyrimidiny chemie   farmakologie   MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• termodynamika MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cyklin-dependentní kinasa 2 MeSH
• pyrazolo(1,5-a)pyrimidine MeSH Prohlížeč
• pyrazoly MeSH
• pyrimidiny MeSH

Base stacking is a major interaction shaping up and stabilizing nucleic acids. During the last decades, base stacking has been extensively studied by experimental and theoretical methods. Advanced quantum-chemical calculations clarified that base stacking is a common interaction, which in the first approximation can be described as combination of the three most basic contributions to molecular interactions, namely, electrostatic interaction, London dispersion attraction and short-range repulsion. There is not any specific π-π energy term associated with the delocalized π electrons of the aromatic rings that cannot be described by the mentioned contributions. The base stacking can be rather reasonably approximated by simple molecular simulation methods based on well-calibrated common force fields although the force fields do not include nonadditivity of stacking, anisotropy of dispersion interactions, and some other effects. However, description of stacking association in condensed phase and understanding of the stacking role in biomolecules remain a difficult problem, as the net base stacking forces always act in a complex and context-specific environment. Moreover, the stacking forces are balanced with many other energy contributions. Differences in definition of stacking in experimental and theoretical studies are explained.

• Klíčová slova
• nucleic acids, quantum-chemical calculations, stacking,
• MeSH
• DNA chemie   MeSH
• kvantová teorie MeSH
• molekulární modely MeSH
• RNA * chemie   MeSH
• simulace molekulární dynamiky MeSH
• termodynamika * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA MeSH
• RNA * MeSH