Flexibility of a biotinylated ligand in artificial metalloenzymes based on streptavidin—an insight from molecular dynamics simulations with classical and ab initio force fields

In the field of enzymatic catalysis, creating activity from a non catalytic scaffold is a daunting task. Introduction of a catalytically active moiety within a protein scaffold offers an attractive means for the creation of artificial metalloenzymes. With this goal in mind, introduction of a biotinylated d6-piano-stool complex within streptavidin (SAV) affords enantioselective artificial transfer-hydrogenases for the reduction of prochiral ketones. Based on an X-ray crystal structure of a highly selective hybrid catalyst, displaying significant disorder around the biotinylated catalyst [η6-(p-cymene)Ru(Biot-p-L)Cl], we report on molecular dynamics simulations to shed light on the protein–cofactor interactions and contacts. The results of these simulations with classical force field indicate that the SAV-biotin and SAV-catalyst complexes are more stable than ligand-free SAV. The point mutations introduced did not affect significantly the overall behavior of SAV and, unexpectedly, the P64G substitution did not provide additional flexibility to the protein scaffold. The metal-cofactor proved to be conformationally flexible, and the S112K or P64G mutants proved to enhance this effect in the most pronounced way. The network of intermolecular hydrogen bonds is efficient at stabilizing the position of biotin, but much less at fixing the conformation of an extended biotinylated ligand. This leads to a relative conformational freedom of the metal-cofactor, and a poorly localized catalytic metal moiety. MD calculations with ab initio potential function suggest that the hydrogen bonds alone are not sufficient factors for full stabilization of the biotin. The hydrophobic biotin-binding pocket (and generally protein scaffold) maintains the hydrogen bonds between biotin and protein

The New Route of the East-West Metro Line in Warsaw

Autorzy artykułu przedstawiają nowy autorski przebieg linii metra na kierunku wschód-zachód w Warszawie. W tekście przedstawiono dotychczasowe prace analityczne wykonane na przestrzeni lat przez ekspertów z różnych środowisk. Na podstawie przytoczonych wyników kreślą własne wnioski, które stanowią punkt wyjścia dla konstrukcji nowego, autorskiego przebiegu nowej linii metra. W artykule przedstawiono zarówno założenia towarzyszące konstrukcji nowego wariantu, sposób wyznaczania przebiegu oraz wstępne wyniki przeprowadzonych obliczeń analitycznych. Prace analityczne oparto o warszawski model ruchu o nazwie Model Transportu Aglomeracji Warszawskiej, a obliczenia przeprowadzono w programie służącym do symulacji ruchu pasażerskiego - VISUM. Przeprowadzone i opisane prace analityczne, jak i osiągnięte wyniki, mają charakter głęboko wstępny, lecz pozwalają spojrzeć optymistycznie na uzasadnienie dalszych prac nad zaproponowanym przebiegiem, który według autorów powinien zostać włączony do grona wariantów rozpatrywanych przez władze miasta.The authors of the article present a new route of the East-West metro line in Warsaw. The text presents previous analytical work done over the years by experts from various disciplines. Based on the quoted results, they draw their own conclusions, which are the starting point for the construction of a new alignment of the new metro route. The article presents the assumptions associated with the construction of the new route, the method of derning proposes alignment and the preliminary results of the analysis. The analysis was based on the Warsaw traffic model called the Agglomeration Transport Model for Warsaw. The traffic calculations and model assignment were carried out in the program used to simulate passenger traffic - VISUM. The data analysis of the traffic flow is from the preliminary stage of the work; however they allow to have an optimistically look at the validation of the further work of the proposed alignment, which by the authors should be included in the group of other variants considered by the city council

Characterization of intermolecular interactions : from dimers to microsolvation models

Intermodular interactions play an important role in many processes at the molecular level. In the contemporary science, there is a growing interest concerning the characteristics of such interactions. Therefore, the computational chemistry can provide answers to many questions, which could not be answered using experimental methods. The Symmetry-Adapted Perturbation Theory (SAPT) method was applied to characterize the energy partitioning in dimers, trimers and microsolvation models. The investigated complexes belong to various classes of compounds, e.g. • dimers of: NH3 ˑˑˑHX, HF-pyridine, cycloalkanes, hypohalous acids; • trimers of: NH3 ˑˑˑNH3ˑˑˑHF or NH3ˑˑˑHFˑˑˑHF; • microsolvation models (biotin - water molecules). The current study summarizes recent years of our research devoted to the intermolecular interactions

Revealing Intra- and Intermolecular Interactions Determining Physico-Chemical Features of Selected Quinolone Carboxylic Acid Derivatives

The intra- and intermolecular interactions of selected quinolone carboxylic acid derivatives were studied in monomers, dimers and crystals. The investigated compounds are well-recognized as medicines or as bases for further studies in drug design. We employed density functional theory (DFT) in its classical formulation to develop gas-phase and solvent reaction field (PCM) models describing geometric, energetic and electronic structure parameters for monomers and dimers. The electronic structure was investigated based on the atoms in molecules (AIM) and natural bond orbital (NBO) theories. Special attention was devoted to the intramolecular hydrogen bonds (HB) present in the investigated compounds. The characterization of energy components was performed using symmetry-adapted perturbation theory (SAPT). Finally, the time-evolution methods of Car–Parrinello molecular dynamics (CPMD) and path integral molecular dynamics (PIMD) were employed to describe the hydrogen bond dynamics as well as the spectroscopic signatures. The vibrational features of the O-H stretching were studied using Fourier transformation of the autocorrelation function of atomic velocity. The inclusion of quantum nuclear effects provided an accurate depiction of the bridged proton delocalization. The CPMD and PIMD simulations were carried out in the gas and crystalline phases. It was found that the polar environment enhances the strength of the intramolecular hydrogen bonds. The SAPT analysis revealed that the dispersive forces are decisive factors in the intermolecular interactions. In the electronic ground state, the proton-transfer phenomena are not favourable. The CPMD results showed generally that the bridged proton is localized at the donor side, with possible proton-sharing events in the solid-phase simulation of stronger hydrogen bridges. However, the PIMD enabled the quantitative estimation of the quantum effects inclusion—the proton position was moved towards the bridge midpoint, but no qualitative changes were detected. It was found that the interatomic distance between the donor and acceptor atoms was shortened and that the bridged proton was strongly delocalized

Microsolvation of Histidine—A Theoretical Study of Intermolecular Interactions Based on AIM and SAPT Approaches

Histidine is unique among amino acids because of its rich tautomeric properties. It participates in essential enzymatic centers, such as catalytic triads. The main aim of the study is the modeling of the change of molecular properties between the gas phase and solution using microsolvation models. We investigate histidine in its three protonation states, microsolvated with 1:6 water molecules. These clusters are studied computationally, in the gas phase and with water as a solvent (Polarizable Continuum Model, PCM) within the Density Functional Theory (DFT) framework. The structural analysis reveals the presence of intra- and intermolecular hydrogen bonds. The Atoms-in-Molecules (AIM) theory is employed to determine the impact of solvation on the charge flow within the histidine, with emphasis on the similarity of the two imidazole nitrogen atoms—topologically not equivalent, they are revealed as electronically similar due to the heterocyclic ring aromaticity. Finally, the Symmetry-Adapted Perturbation Theory (SAPT) is used to examine the stability of the microsolvation clusters. While electrostatic and exchange terms dominate in magnitude over polarization and dispersion, the sum of electrostatic and exchange term is close to zero. This makes polarization the factor governing the actual interaction energy. The most important finding of this study is that even with microsolvation, the polarization induced by the presence of implicit solvent is still significant. Therefore, we recommend combined approaches, mixing explicit water molecules with implicit models

Intramolecular hydrogen bonds properties in selected N-oxides of quinoline derivatives

In the current article we would like to summarize our research shedding light onto properties of intramolecular hydrogen bonds present in N-oxide quinoline derivatives. The compounds for the current study were chosen to contain diverse types of hydrogen bonds. Therefore, in the current study we analyze three kinds of hydrogen bonding and their properties. It is well known, that the presence of intramolecular hydrogen bonds stabilizes conformations of molecules. Substituent effects (inductive and steric) influence the strength of the H-bonding as well as its features. Moreover, the intramolecular hydrogen bond in the studied N-oxides belongs to the family of resonance assisted hydrogen bonds (RAHB). Our short overview presents the summary of results obtained for twelve N-oxides of quinoline derivatives. Quantum-chemical simulations were performed on the basis of static models (classical DFT and MP2 approaches) as well as ab initio molecular dynamics (Car-Parrinello MD). The metadynamics method was applied to reproduce the maps of free energy for the motion of the bridged proton. The computations were performed in the gas and in the crystalline phases. Electronic ground state is a natural framework in which chemical compounds exist most of the time. However, in many chemical species we observe a spontaneous internal reorganization of their chemical bonds and atoms e.g. proton transfer phenomenon and the appearance of tautomeric forms already in the ground state. Therefore, it was interesting to investigate some N-oxides in the excited electron state knowing that they exhibit excited- state-induced proton transfer (ESIPT effect). At the end of the article we draw some conclusions related to the intramolecular H-bond properties present in the discussed N-oxides of quinoline derivatives