Molecular Structure and Electronic Properties of Porphyrin-Thiophene-Perylene Using Quantum Chemical Calculation

This study aimed to design a new series of compounds consisting of a porphyrin macrocycle linked to a perylene unit via a thiophenic bridge. The structural and electronic properties of the molecules, and the effects of mono- and di-substituents R on C3 and R′ on C4 of the thiophene ring were investigated using a quantum calculation approach. The results from the method validation revealed that using the density functional theory approach at B3LYP/6–31G(d) data set was the optimal one, considering the accuracy attained and maintaining the computer time required within tractable limits. The results from the B3LYP/6–31G(d) approach indicated that significant changes of the torsion angle between the molecular planes of the porphyrin and perylene rings, compared to that of the unsubstituted derivatives, were found in the di-substituted systems bearing R = R′ = −OCH3 and −NH2, and in a mono-substituted system having R = −H and R′=−NH2. The symmetric di-substitution does not provide a significantly lower HOMO-LUMO energy gap (ΔEg). Noticeable decreases in ΔEg were found only with the substitution patterns of: R, R′ = −OCH3, −H; −OH, −H; −N(CH3)2, −H; −H, −NH2. UV-visible spectra of all derivatives exhibited characteristic absorption maxima of the free bases of porphyrin and perylene

Substrate Induced Structural and Dynamics Changes in Human Phosphomevalonate Iinase and Implications for Mechanism

Phosphomevalonate kinase (PMK) catalyzes an essential step in the mevalonate pathway, which is the only pathway for synthesis of isoprenoids and steroids in humans. PMK catalyzes transfer of the γ-phosphate of ATP to mevalonate 5-phosphate (M5P) to form mevalonate 5-diphosphate. Bringing these phosphate groups in proximity to react is especially challenging, given the high negative charge density on the four phosphate groups in the active site. As such, conformational and dynamics changes needed to form the Michaelis complex are of mechanistic interest. Herein, we report the characterization of substrate induced changes (Mg-ADP, M5P, and the ternary complex) in PMK using NMR-based dynamics and chemical shift perturbation measurements. Mg-ADP and M5P Kd\u27s were 6–60 μM in all complexes, consistent with there being little binding synergy. Binding of M5P causes the PMK structure to compress (τc = 13.5 nsec), whereas subsequent binding of Mg-ADP opens the structure up (τc = 15.6 nsec). The overall complex seems to stay very rigid on the psec-nsec timescale with an average NMR order parameter of S2 ∼0.88. Data are consistent with addition of M5P causing movement around a hinge region to permit domain closure, which would bring the M5P domain close to ATP to permit catalysis. Dynamics data identify potential hinge residues as H55 and R93, based on their low order parameters and their location in extended regions that connect the M5P and ATP domains in the PMK homology model. Likewise, D163 may be a hinge residue for the lid region that is homologous to the adenylate kinase lid, covering the “Walker-A” catalytic loop. Binding of ATP or ADP appears to cause similar conformational changes; however, these observations do not indicate an obvious role for γ-phosphate binding interactions. Indeed, the role of γ-phosphate interactions may be more subtle than suggested by ATP/ADP comparisons, because the conservative O to NH substitution in the β-γ bridge of ATP causes a dramatic decrease in affinity and induces few chemical shift perturbations. In terms of positioning of catalytic residues, binding of M5P induces a rigidification of Gly21 (adjacent to the catalytically important Lys22), although exchange broadening in the ternary complex suggests some motion on a slower timescale does still occur. Finally, the first nine residues of the N-terminus are highly disordered, suggesting that they may be part of a cleavable signal or regulatory peptide sequence. Proteins 2009. © 2008 Wiley-Liss, Inc

Dynamics simulations of excited-state triple proton transfer in 7-azaindole complexes with water, water–methanol and methanol

Excited-state triple proton transfer (ESTPT) reactions in 7-azaindole (7AI) complexed with two water, with one water and one methanol, and with two methanol molecules were investigated by dynamics simulations in the first excited state computed with the second order algebraic-diagrammatic construction (ADC (2)) method. The results show that photoexcitation may trigger ultrafast an asynchronous concerted proton transfer via two solvent molecules along an intermolecular hydrogen-bonded network. The probability of occurrence of ESTPT ranges from 32% for 7AI(H2O–MeOH) to 64% for 7AI(MeOH)2. The average time for completing the ESTPT varies between 58 and 85 fs depending on the complex. The proton transfer (rather than hydrogen transfer) nature of the reaction was suggested by the nonexistence of crossings between the ππ* and πσ* states

Molecular Docking and NMR Binding Studies to Identify Novel Inhibitors of Human Phosphomevalonate Kinase

Phosphomevalonate kinase (PMK) phosphorylates mevalonate-5-phosphate (M5P) in the mevalonate pathway, which is the sole source of isoprenoids and steroids in humans. We have identified new PMK inhibitors with virtual screening, using autodock. Promising hits were verified and their affinity measured using NMR-based 1H–15N heteronuclear single quantum coherence (HSQC) chemical shift perturbation and fluorescence titrations. Chemical shift changes were monitored, plotted, and fitted to obtain dissociation constants (Kd). Tight binding compounds with Kd’s ranging from 6–60 μM were identified. These compounds tended to have significant polarity and negative charge, similar to the natural substrates (M5P and ATP). HSQC cross peak changes suggest that binding induces a global conformational change, such as domain closure. Compounds identified in this study serve as chemical genetic probes of human PMK, to explore pharmacology of the mevalonate pathway, as well as starting points for further drug development

A detailed binding free energy study of 2 : 1 ligand–DNA complex formation by experiment and simulation

In 2004, we used NMR to solve the structure of the minor groove binder thiazotropsin A bound in a 2 : 1 complex to the DNA duplex, d(CGACTAGTCG)2. In this current work, we have combined theory and experiment to confirm the binding thermodynamics of this system. Molecular dynamics simulations that use polarizable or non-polarizable force fields with single and separate trajectory approaches have been used to explore complexation at the molecular level. We have shown that the binding process invokes large conformational changes in both the receptor and ligand, which is reflected by large adaptation energies. This is compensated for by the net binding free energy, which is enthalpy driven and entropically opposed. Such a conformational change upon binding directly impacts on how the process must be simulated in order to yield accurate results. Our MM-PBSA binding calculations from snapshots obtained from MD simulations of the polarizable force field using separate trajectories yield an absolute binding free energy (-15.4 kcal mol-1) very close to that determined by isothermal titration calorimetry (-10.2 kcal mol-1). Analysis of the major energy components reveals that favorable non-bonded van der Waals and electrostatic interactions contribute predominantly to the enthalpy term, whilst the unfavorable entropy appears to be driven by stabilization of the complex and the associated loss of conformational freedom. Our results have led to a deeper understanding of the nature of side-by-side minor groove ligand binding, which has significant implications for structure-based ligand development

A DFT-based Analysis of Metals Adsorption on Chitosan Monomer

The generation of waste electrical and electronic equipment (WEEE or E-waste) has been noted as an increasing category of waste. In this work, the density functional theory (DFT) was used to investigate the adsorption process between chitosan (CS) and metals at the B3LYP level with 6-31G(d,p) and LANL2DZ basis sets. The effect of solvent was included using the polarizable continuum model (PCM) consisting of water. Ag+, As3+, Ba2+, Be2+, Cd2+, Co2+, Cr3+, Cu2+, Hg2+, Li+, Mn2+, Ni2+, Pb2+, Pd2+, Sb3+, Sn2+, Sr2+, Tl+, and Zn2+ have been selected to be studied because of high impact in E-waste. Different analyses were carried out: adsorption energy, HOMO-LUMO energy gaps, hardness, softness, frontier molecular orbitals, and molecular electrostatic potential (MEP), and all of which are necessary to predict the formation of complexes. The interaction between CS and metal species was shown in almost all cases as covalent partial. In addition, all metals were placed closeer to the nitrogen atom than the oxygen atom of CS because the charge density of the nitrogen is increased in the formation of the Schiff base. Finally, the monomer derived from CS has good stability in water and is, therefore, considered as a good material in the field of environmental pollution

Molecular Dynamics simulations of supercritical ammonia and metal-ammonia solutions

The results of Molecular Dynamics simulations of supercritical ammonia are reported for the first time. Qualitative agreement is found with neutron diffraction studies, the only experimental evidence on the structure of supercritical ammonia, so far. Based on the experiences with aqueous electrolyte solutions, it is discussed how the potentials describing ion-ammonia interactions in dilute and concentrated metal-ammonia solutions at subcritical conditions have to be modified for supercritical simulations.Вперше представлені результати моделювання методом молекулярної динаміки аміаку в надкритичному стані. Встановлено якісне узгодження з дослідженнями за дифракцією нейтронів, які є єдиним експериментальним свідченням про структуру аміаку у надкритичному стані. На основі відомих даних про водні розчини електролітів обговорюється питання про те, в який спосіб необхідно модифікувати потенціали, що описують взаємодії іон-аміак у розведених та концентрованих розчинах металів у аміаку, з метою їх застосування у моделюванні аміаку в надкритичному стані