We report the first complete description of the molecular mechanisms behind the transition of the N-methyl-d-aspartate (NMDA) receptor from the state where the transmembrane domain (TMD) and the ion channel are in the open configuration to the relaxed unliganded state where the channel is closed. Using an aggregate of nearly 1 µs of unbiased all-atom implicit membrane and solvent molecular dynamics (MD) simulations we identified distinct structural states of the NMDA receptor and revealed functionally important residues (GluN1/Glu522, GluN1/Arg695, and GluN2B/Asp786). The role of the "clamshell" motion of the ligand binding domain (LBD) lobes in the structural transition is supplemented by the observed structural similarity at the level of protein domains during the structural transition, combined with the overall large rearrangement necessary for the opening and closing of the receptor. The activated and open states of the receptor are structurally similar to the liganded crystal structure, while in the unliganded receptor the extracellular domains perform rearrangements leading to a clockwise rotation of up to 45 degrees around the longitudinal axis of the receptor, which closes the ion channel. The ligand-induced rotation of extracellular domains transferred by LBD-TMD linkers to the membrane-anchored ion channel is responsible for the opening and closing of the transmembrane ion channel, revealing the properties of NMDA receptor as a finely tuned molecular machine.

• Klíčová slova
• NMDA receptor transition, glutamate receptor gating, molecular dynamics simulations, molecular modeling, open and closed state,
• MeSH
• krysa rodu Rattus MeSH
• receptory N-methyl-D-aspartátu chemie   metabolismus   MeSH
• simulace molekulární dynamiky * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• receptory N-methyl-D-aspartátu MeSH

Thermotropic polyurethanes with mesogenic groups in side chains were prepared from two diisocyanates and four diols with stoichiometric ratios of reactive isocyanate (NCO) and hydroxy (OH) groups. Their thermal behavior was determined by differential scanning calorimetry. The effect of structure modifications of the diisocyanates and diols, in particular changes in the mesogen, were investigated. Introduction of mesogenic segments into the polymers suppresses the ordering. Stiff end substituents (phenyl and alkoxy groups) of the mesogens stabilize the mesophases to such an extent that the negative influence of long polymer chains is compensated and the liquid-crystalline properties are recovered. All-atom molecular dynamics simulations in the Cerius2 modeling environment were carried out to characterize the structures of the polymers. Analysis of the dynamic trajectories at 20, 100, 120 and 170 degrees C revealed changes in conformation of macromolecules, which correlate with DSC measurements.

• MeSH
• isokyanatany chemie   MeSH
• kalorimetrie MeSH
• molekulární konformace MeSH
• molekulární modely * MeSH
• molekulární struktura MeSH
• počítačová simulace MeSH
• polyurethany chemie   MeSH
• teplota MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• isokyanatany MeSH
• polyurethany MeSH

Glutathione (GSH) is a common antioxidant and its biological activity depends on the conformation and protonation state. We used molecular dynamics, Raman and Raman optical activity (ROA) spectroscopies to investigate GSH structural changes in a broad pH range. Factor analysis of the spectra provided protonation constants (2.05, 3.45, 8.62, 9.41) in good agreement with previously published values. Following the analysis, spectra of differently protonated forms were obtained by extrapolation. The complete deprotonation of the thiol group above pH 11 was clearly visible in the spectra; however, many spectral features did not change much with pH. Experimental spectra at various pH values were decomposed into the simulated ones, which allowed us to study the conformer populations and quality of molecular dynamics (MD). According to this combined ROA/MD analysis conformation of the GSH backbone is affected by the pH changes only in a limited way. The combination of ROA with the computations thus has the potential to improve the MD force field and obtain more accurate populations of the conformer species. The methodology can be used for any molecule, but for a more detailed insight better computational techniques are needed in the future.

• Klíčová slova
• Raman optical activity, density functional theory, glutathione, molecular dynamics, spectra modeling,
• MeSH
• glutathion MeSH
• molekulární konformace MeSH
• optická otáčivost MeSH
• Ramanova spektroskopie * metody   MeSH
• simulace molekulární dynamiky * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• glutathion MeSH

Riboswitches often occur in the 5'-untranslated regions of bacterial mRNA where they regulate gene expression. The preQ(1) riboswitch controls the biosynthesis of a hypermodified nucleoside queuosine in response to binding the queuosine metabolic intermediate. Structures of the ligand-bound and ligand-free states of the preQ(1) riboswitch from Thermoanaerobacter tengcongensis were determined recently by X-ray crystallography. We used multiple, microsecond-long molecular dynamics simulations (29 μs in total) to characterize the structural dynamics of preQ(1) riboswitches in both states. We observed different stabilities of the stem in the bound and free states, resulting in different accessibilities of the ribosome-binding site. These differences are related to different stacking interactions between nucleotides of the stem and the associated loop, which itself adopts different conformations in the bound and free states. We suggest that the loop not only serves to bind preQ(1) but also transmits information about ligand binding from the ligand-binding pocket to the stem, which has implications for mRNA accessibility to the ribosome. We explain functional results obscured by a high salt crystallization medium and help to refine regions of disordered electron density, which demonstrates the predictive power of our approach. Besides investigating the functional dynamics of the riboswitch, we have also utilized this unique small folded RNA system for analysis of performance of the RNA force field on the μs time scale. The latest AMBER parmbsc0χ(OL3) RNA force field is capable of providing stable trajectories of the folded molecule on the μs time scale. On the other hand, force fields that are not properly balanced lead to significant structural perturbations on the sub-μs time scale, which could easily lead to inappropriate interpretation of the simulation data.

• MeSH
• bakteriální RNA chemie   MeSH
• krystalografie rentgenová MeSH
• molekulární modely MeSH
• riboswitch * MeSH
• simulace molekulární dynamiky * MeSH
• Thermoanaerobacter chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• bakteriální RNA MeSH
• riboswitch * MeSH

A computational method of modeling random coils of hyaluronan was developed based on the molecular-dynamics simulations. An oligosaccharide of 48 monosaccharide units was equilibrated within a 70-100ns simulation and randomly chosen pieces of this molecule from different simulation frames were combined to constitute a long polysaccharide chain, both for hyaluronan and its non-ionic analog containing glucose instead of glucuronic acid. The dihedral angles of the glycoside connections of the pieces obeyed the statistics deduced from the simulation. The simulations were performed at various concentrations of NaCl and MgCl2. The calculated radii of gyration show a striking agreement with experimental data from the literature and indicate a key importance of the polymer-ion interactions for the random-coil conformation, but a low influence of the excluded volume of the chain and the carboxylate-groups repulsion. The method has thus the potential to become a versatile tool of modeling macromolecules of various semirigid polymers.

• Klíčová slova
• Dihedral angle, Electrolyte, Hyaluronan, Molecular dynamics, Radius of gyration,
• MeSH
• elektrolyty chemie   MeSH
• kyselina hyaluronová chemie   MeSH
• molekulární konformace MeSH
• simulace molekulární dynamiky * MeSH
• software MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• elektrolyty MeSH
• kyselina hyaluronová MeSH

We provide a high-level survey of multiscale molecular visualization techniques, with a focus on application-domain questions, challenges, and tasks. We provide a general introduction to molecular visualization basics and describe a number of domain-specific tasks that drive this work. These tasks, in turn, serve as the general structure of the following survey. First, we discuss methods that support the visual analysis of molecular dynamics simulations. We discuss, in particular, visual abstraction and temporal aggregation. In the second part, we survey multiscale approaches that support the design, analysis, and manipulation of DNA nanostructures and related concepts for abstraction, scale transition, scale-dependent modeling, and navigation of the resulting abstraction spaces. In the third part of the survey, we showcase approaches that support interactive exploration within large structural biology assemblies up to the size of bacterial cells. We describe fundamental rendering techniques as well as approaches for element instantiation, visibility management, visual guidance, camera control, and support of depth perception. We close the survey with a brief listing of important tools that implement many of the discussed approaches and a conclusion that provides some research challenges in the field.

• Klíčová slova
• DNA nanotechnology, modelitics, molecular dynamics, molecular visualization, visual abstraction,
• MeSH
• Bacteria MeSH
• DNA ultrastruktura   MeSH
• lidé MeSH
• molekulární modely MeSH
• nanostruktury * MeSH
• proteiny chemie   MeSH
• simulace molekulární dynamiky * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• DNA MeSH
• proteiny MeSH

Pharmacophore models are widely used for the identification of promising primary hits in compound large libraries. Recent studies have demonstrated that pharmacophores retrieved from protein-ligand molecular dynamic trajectories outperform pharmacophores retrieved from a single crystal complex structure. However, the number of retrieved pharmacophores can be enormous, thus, making it computationally inefficient to use all of them for virtual screening. In this study, we proposed selection of distinct representative pharmacophores by the removal of pharmacophores with identical three-dimensional (3D) pharmacophore hashes. We also proposed a new conformer coverage approach in order to rank compounds using all representative pharmacophores. Our results for four cyclin-dependent kinase 2 (CDK2) complexes with different ligands demonstrated that the proposed selection and ranking approaches outperformed the previously described common hits approach. We also demonstrated that ranking, based on averaged predicted scores obtained from different complexes, can outperform ranking based on scores from an individual complex. All developments were implemented in open-source software pharmd.

• Klíčová slova
• molecular dynamics, pharmacophore, virtual screening,
• MeSH
• cyklin-dependentní kinasa 2 chemie   metabolismus   MeSH
• inhibitory proteinkinas chemie   farmakologie   MeSH
• knihovny malých molekul chemie   farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• objevování léků metody   MeSH
• počítačová simulace MeSH
• simulace molekulární dynamiky * MeSH
• simulace molekulového dockingu metody   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cyklin-dependentní kinasa 2 MeSH
• inhibitory proteinkinas MeSH
• knihovny malých molekul MeSH
• ligandy MeSH

Hydrogen-Deuterium exchange mass spectrometry's (HDX-MS) utility in identifying and characterizing protein-small molecule interaction sites has been established. The regions that are seen to be protected from exchange upon ligand binding indicate regions that may be interacting with the ligand, giving a qualitative understanding of the ligand binding pocket. However, quantitatively deriving an accurate high-resolution structure of the protein-ligand complex from the HDX-MS data remains a challenge, often limiting its use in applications such as small molecule drug design. Recent efforts have focused on the development of methods to quantitatively model Hydrogen-Deuterium exchange (HDX) data from computationally modeled structures to garner atomic level insights from peptide-level resolution HDX-MS. One such method, HDX ensemble reweighting (HDXer), employs maximum entropy reweighting of simulated HDX data to experimental HDX-MS to model structural ensembles. In this study, we implement and validate a workflow which quantitatively leverages HDX-MS data to accurately model protein-small molecule ligand interactions. To that end, we employ a strategy combining computational protein-ligand docking, molecular dynamics simulations, HDXer, and dimensional reduction and clustering approaches to extract high-resolution drug binding poses that most accurately conform with HDX-MS data. We apply this workflow to model the interaction of ERK2 and FosA with small molecule compounds and inhibitors they are known to bind. In five out of six of the protein-ligand pairs tested, the HDX derived protein-ligand complexes result in a ligand root-mean-square deviation (RMSD) within 2.5 Å of the known crystal structure ligand.

• Klíčová slova
• Computational Docking, ERK2, FosAKP, HDX-MS, HDXer, Hydrogen−Deuterium Exchange, Maximum Entropy Reweighting, Molecular Dynamics Simulations, Protein−Ligand Modeling, Protein−Small Molecule Interactions, Structure Based Drug Design,
• MeSH
• konformace proteinů MeSH
• ligandy MeSH
• proteiny chemie   metabolismus   MeSH
• simulace molekulární dynamiky * MeSH
• simulace molekulového dockingu MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• vodík/deuteriová výměna a hmotnostní spektrometrie * metody   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ligandy MeSH
• proteiny MeSH

In this study, quantitative structure-activity relationship studies which make use of molecular dynamics trajectories were performed on a set of 54 glucokinase protein activators. The conformations obtained by molecular dynamics simulation were superimposed according to the twelve alignments tested in a virtual three-dimensional box comprised of 2 Å cells. The models were generated by the technique that combines genetic algorithms and partial least squares. The best alignment models generated with a determination coefficient (r(2)) between 0.674 and 0.743 and cross-validation (q(2)) between 0.509 and 0.610, indicating good predictive capacity. The 4D-QSAR models developed in this study suggest novel molecular regions to be explored in the search for better glucokinase activators.

• Klíčová slova
• diabetes mellitus, glucokinase, glucokinase activators and 4D-QSAR, type 2 diabetes,
• MeSH
• aktivace enzymů MeSH
• glukokinasa metabolismus   MeSH
• kvantitativní vztahy mezi strukturou a aktivitou MeSH
• lidé MeSH
• simulace molekulární dynamiky MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• glukokinasa MeSH

In this study, we have carried out a combined experimental and computational investigation to elucidate several bred-in-the-bone ideas standing out in rational design of novel cationic surfactants as antibacterial agents. Five 3-hydroxypyridinium salts differing in the length of N-alkyl side chain have been synthesized, analyzed by high performance liquid chromatography, tested for in vitro activity against a panel of pathogenic bacterial and fungal strains, computationally modeled in water by a SCRF B3LYP/6-311++G(d,p) method, and evaluated by a systematic QSAR analysis. Given the results of this work, the hypothesis suggesting that higher positive charge of the quaternary nitrogen should increase antimicrobial efficacy can be rejected since 3-hydroxyl group does increase the positive charge on the nitrogen but, simultaneously, it significantly derogates the antimicrobial activity by lowering the lipophilicity and by escalating the desolvation energy of the compounds in comparison with non-hydroxylated analogues. Herein, the majority of the prepared 3-hydroxylated substances showed notably lower potency than the parent pyridinium structures, although compound 8 with C12 alkyl chain proved a distinctly better antimicrobial activity in submicromolar range. Focusing on this anomaly, we have made an effort to reveal the reason of the observed activity through a molecular dynamics simulation of the interaction between the bacterial membrane and compound 8 in GROMACS software.

• Klíčová slova
• Antimicrobials, Molecular dynamics, Molecular modeling, QSAR, Quaternary ammoniums salts, Surfactants,
• MeSH
• antibakteriální látky chemie   farmakologie   toxicita   MeSH
• Bacteria účinky léků   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• houby účinky léků   MeSH
• hydrofobní a hydrofilní interakce MeSH
• křečci praví MeSH
• kvantitativní vztahy mezi strukturou a aktivitou * MeSH
• molekulární konformace MeSH
• pyridiny chemie   farmakologie   toxicita   MeSH
• simulace molekulární dynamiky * MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 3-hydroxypyridine MeSH Prohlížeč
• antibakteriální látky MeSH
• pyridiny MeSH