Implication of Crystal Water Molecules in Inhibitor Binding at ALR2 Active Site

Water molecules play a crucial role in mediating the interaction between a ligand and a macromolecule. The solvent environment around such biomolecule controls their structure and plays important role in protein-ligand interactions. An understanding of the nature and role of these water molecules in the active site of a protein could greatly increase the efficiency of rational drug design approaches. We have performed the comparative crystal structure analysis of aldose reductase to understand the role of crystal water in protein-ligand interaction. Molecular dynamics simulation has shown the versatile nature of water molecules in bridge H bonding during interaction. Occupancy and life time of water molecules depend on the type of cocrystallized ligand present in the structure. The information may be useful in rational approach to customize the ligand, and thereby longer occupancy and life time for bridge H-bonding

Non-radiative decay and stability of NN-heterocyclic carbene iridium(III) complexes

Devices based on deep-blue emitting iridium (III) complexes with N-heterocyclic carbene (NHC) ligands have recently been shown to give excellent performance as phosphorescent organic light-emitting diodes (PHOLEDs). To facilitate the design of even better deep-blue phosphorescent emitters we carried out density functional theory (DFT) calculations of the lowest triplet ($T_1$) potential-energy surfaces (PES) upon lengthening the iridium-ligand (Ir-C) bonds. Relativistic time dependent-DFT (TDDFT) calculations demonstrate that this changes the nature of $T_1$ from a highly-emissive metal-to-ligand charge transfer ($^3$MLCT) state to a metal centered ($^3$MC) state where the radiative decay rate is orders of magnitude slower than that of the $^3$MLCT state. We identify the elongation of an Ir-C bond on the NHC group as the pathway with lowest energy barrier between the $^3$MLCT and $^3$MC states for all complexes studied and show that the barrier height is correlated with the experimentally measured non-radiative decay rate. This suggests that the thermal population of $^3$MC states is the dominant non-radiative decay mechanism at room temperature. We show that the $^3$MLCT $\rightarrow$ $^3$MC transition is reversible, in marked contrast to other deep blue phosphors containing coordinating nitrogen atoms, where the population of $^3$MC states breaks Ir-N bonds. This suggests that, as well as improved efficiency, blue PHOLEDs containing phosphors where the metal is only coordinated by carbon atoms will have improved device lifetimes.Comment: 15 pages, 4 figures, 3 table

A Diffusion-Based Approach to Geminate Recombination of Heme Proteins with Small Ligands

A model of postphotodissociative monomolecular (geminate) recombination of heme proteins with small ligands (NO, O2 or CO) is represented. The non-exponential decay with time for the probability to find a heme in unbound state is interpreted in terms of diffusion-like migration of ligabs physics/0212040 and between protein cavities. The temporal behavior for the probability is obtained from numerical simulation and specified by two parameters: the time \tau_{reb} of heme-ligand rebinding for the ligand localized inside the heme pocket and the time \tau_{esc} of ligand escape from the pocket. The model is applied in the analysis of available experimental data for geminate reoxygenation of human hemoglobin HbA. Our simulation is in good agreement with the measurements. The analysis shows that the variation in pH of the solution (6.0<pH<9.4) results in considerable changes for \tau_{reb} from 0.36 ns (at pH=8.5) up to 0.5 ns (pH=6.0) but effects slightly on the time \tau_{esc} (\tau_{esc} ~ 0.88 ns).Comment: 8 pages with 4 figures, submitted to Chem. Phy

Efficiency of initiating cell adhesion in hydrodynamic flow

We theoretically investigate the efficiency of initial binding between a receptor-coated sphere and a ligand-coated wall in linear shear flow. The mean first passage time for binding decreases monotonically with increasing shear rate. Above a saturation threshold of the order of a few 100 receptor patches, the binding efficiency is enhanced only weakly by increasing their number and size, but strongly by increasing their height. This explains why white blood cells in the blood flow adhere through receptor patches localized to the tips of microvilli, and why malaria-infected red blood cells form elevated receptor patches (knobs).Comment: 4 pages, Revtex, 4 Postscript figures included, to appear in PR

Dinuclear Re(I) Complexes as New Electrocatalytic Systems for CO2 Reduction

A family of dinuclear tricarbonyl rhenium (I) complexes containing bridging 1,2-diazine ligand and halide anions as ancillary ligands and able to catalyze CO2 reduction is presented. Electrochemical studies show that the highest catalytic efficiency is obtained for the complex containing the 4,5-bipenthyl-pyridazine and iodide as ancillary halogen ligands. This complex gives rise to TOF=15 s−1 that clearly outperforms the values reported for the benchmark mononuclear Re(CO)3Cl(bpy) (11.1 s−1). The role of the substituents on the pyridazine ligand and the nature of the bridging halide ligands on the catalytic activity have been deeply investigated through a systematic study on the structure-properties relationship to understand the improved catalytic efficiencies of this class of complexes

Local dynamical lattice instabilities: Prerequisites for resonant pairing superconductivity

Fluctuating local diamagnetic pairs of electrons, embedded in a Fermi sea, are candidates for non-phonon-mediated superconductors without the stringent conditions on Tc which arise in phonon-mediated BCS classical low-Tc superconductors. The local accumulations of charge, from which such diamagnetic fluctuations originate, are irrevocably coupled to local dynamical lattice instabilities and form composite charge-lattice excitations of the system. For a superconducting phase to be realized, such excitations must be itinerant spatially phase-coherent modes. This can be achieved by resonant pair tunneling in and out of polaronic cation-ligand sites. Materials in which superconductivity driven by such local lattice instability can be expected, have a Tc which is controlled by the phase stiffness rather than the amplitude of the diamagnetic pair fluctuations. Above Tc, a pseudogap phase will be maintained up to a T*, where this pairing amplitude disappears. We discuss the characteristic local charge and lattice properties which characterize this pseudogap phase and which form the prerequisites for establishing a phase-coherent macroscopic superconducting state.Comment: 15 pages, 13 figure

Evolution of sparsity and modularity in a model of protein allostery

The sequence of a protein is not only constrained by its physical and biochemical properties under current selection, but also by features of its past evolutionary history. Understanding the extent and the form that these evolutionary constraints may take is important to interpret the information in protein sequences. To study this problem, we introduce a simple but physical model of protein evolution where selection targets allostery, the functional coupling of distal sites on protein surfaces. This model shows how the geometrical organization of couplings between amino acids within a protein structure can depend crucially on its evolutionary history. In particular, two scenarios are found to generate a spatial concentration of functional constraints: high mutation rates and fluctuating selective pressures. This second scenario offers a plausible explanation for the high tolerance of natural proteins to mutations and for the spatial organization of their least tolerant amino acids, as revealed by sequence analyses and mutagenesis experiments. It also implies a faculty to adapt to new selective pressures that is consistent with observations. Besides, the model illustrates how several independent functional modules may emerge within a same protein structure, depending on the nature of past environmental fluctuations. Our model thus relates the evolutionary history and evolutionary potential of proteins to the geometry of their functional constraints, with implications for decoding and engineering protein sequences

Disulfide-linked allosteric modulators for multi-cycle kinetic control of DNA-based nanodevices

Nature employs sulfur switches, that is, redox-active disulfides, to kinetically control biological pathways in a highly efficient and reversible way. Inspired by this mechanism, we describe herein a DNA-based synthetic nanodevice that acts as a sulfur switch and can be temporally controlled though redox regulation. To do this, we rationally designed disulfide DNA strands (modulators) that hybridize to a ligand-binding DNA nanodevice and act as redox-active allosteric regulators inducing the nanodevice to release or load its ligand. Upon reduction, the allosteric modulator spontaneously de-hybridizes from the nanodevice and, as a result, its effect is transient. The system is reversible and has an unprecedented high tolerance to waste products and displays transient behavior for over 40 cycles without significant loss of efficiency. Kinetic control of DNA-based ligand-binding nanodevices through purely chemical reactions paves the way for temporal regulation of more complex chemical pathways