Structural analysis of hERG channel blockers and the implications for drug design.

The repolarizing current (Ikr) produced by the hERG potassium channel forms a major component of the cardiac action potential and blocking this current by small molecule drugs can lead to life-threatening cardiotoxicity. Understanding the mechanisms of drug-mediated hERG inhibition is essential to develop a second generation of safe drugs, with minimal cardiotoxic effects. Although various computational tools and drug design guidelines have been developed to avoid binding of drugs to the hERG pore domain, there are many other aspects that are still open for investigation. This includes the use computational modelling to study the implications of hERG mutations on hERG structure and trafficking, the interactions of hERG with hERG chaperone proteins and with membrane-soluble molecules, the mechanisms of drugs that inhibit hERG trafficking and drugs that rescue hERG mutations. The plethora of available experimental data regarding all these aspects can guide the construction of much needed robust computational structural models to study these mechanisms for the rational design of safe drugs.

Copper (0) Mediated Single Electron Transfer-Living Radical Polymerization of Methyl Methacrylate: Functionalized Graphene as a Convenient Tool for Radical Initiator.

Polymer nanocomposites have been synthesized by the covalent addition of bromide-functionalized graphene (Graphene-Br) through the single electron transfer-living radical polymerization technique (SET-LRP). Graphite functionalized with bromide for the first time via an efficient route using mild reagents has been designed to develop a graphene based radical initiator. The efficiency of sacrificial initiator (ethyl α-bromoisobutyrate) has also been compared with a graphene based initiator towards monitoring their Cu(0) mediated controlled molecular weight and morphological structures through mass spectroscopy (MOLDI-TOF) and field emission scanning electron microscopy (FE-SEM) analysis, respectively. The enhancement in thermal stability is observed for graphene-grafted-poly(methyl methacrylate) (G-g-PMMA) at 392 °C, which may be due to the influence ofthe covalent addition of graphene, whereas the sacrificial initiator used to synthesize G-graft-PMMA (S) has low thermal stability as analyzed by TGA. A significant difference is noticed on their glass transition and melting temperatures by DSC. The controlled formation and structural features of the polymer-functionalized-graphene is characterized by Raman, FT-IR, UV-Vis spectroscopy, NMR, and zeta potential measurements. The wettability measurements of the novel G-graft-PMMA on leather surface were found to be better in hydrophobic nature with a water contact angle of 109 ± 1°.

An experimental and steered molecular dynamics simulation approach to histidine assisted liquid-phase exfoliation of graphite into few-layer graphene.

A simple and green approach to exfoliate graphite in water was developed by its reaction with an amino acid, histidine (His), resulting in the spatial expansion of the interlayer space. Subsequent sonication led to few-layered nanosheets of graphene in water. Steered molecular dynamics (MD) simulations revealed that the exfoliating graphene sheet underwent sheered motion before completely scaling off from the other layer.

Protein Arrangement Effects on the Exciton Dynamics in the PE555 Complex.

The environmental coupling of the phycobiliprotein antenna complex PE555 and its excitonic energy transfer mechanisms are studied in detail. Molecular dynamics simulations were performed followed by calculations of the vertical transition energies along the classical ground-state trajectory. To this end, the distributions of energy levels for the PE555 complex were found to be similar to those of the PE545 complex despite the clear differences in the respective protein structures. In the PE555 complex the two αß monomers are rotated by ∼73° compared to the PE545 structure leading to a water filled channel. Moreover, the connections between the bilins, which act as pigments in these aggregates, and the protein show clear differences in the two structures. Analyzing the coupling of the individual chromophores to the protein environment, however, yielded similar spectral densities in the two protein complexes. In addition, the partial transition charges of the involved bilins have been determined in order to calculate the electronic couplings using the transition charges from electrostatic potentials (TrEsp) method. For comparison purposes, the couplings have been extracted using the point-dipole approximation as well. On average the coupling values predicted by the dipole approximation are slightly larger than those from the TrEsp method leading to enhanced population decay rates as tested in ensemble-averaged wave packet dynamics. Moreover, the exciton dynamics in the PE555 structure is significantly slower than in the PE545 complex due to the smaller coupling values induced by the dissimilar arrangements of the monomers.

Relation between Dephasing Time and Energy Gap Fluctuations in Biomolecular Systems.

Excitation energy and charge transfer are fundamental processes in biological systems. Because of their quantum nature, the effect of dephasing on these processes is of interest especially when trying to understand their efficiency. Moreover, recent experiments have shown quantum coherences in such systems. As a first step toward a better understanding, we studied the relationship between dephasing time and energy gap fluctuations of the individual molecular subunits. A larger set of molecular simulations has been investigated to shed light on this dependence. This set includes bacterio-chlorophylls in Fenna-Matthews-Olson complexes, the PE545 aggregate, the LH2 complexes, DNA, photolyase, and cryptochromes. For the individual molecular subunits of these aggregates it has been confirmed quantitatively that an inverse proportionality exists between dephasing time and average gap energy fluctuation. However, for entire complexes including the respective intermolecular couplings, such a relation still needs to be verified.

Influence of Force Fields and Quantum Chemistry Approach on Spectral Densities of BChl a in Solution and in FMO Proteins.

Studies on light-harvesting (LH) systems have attracted much attention after the finding of long-lived quantum coherences in the exciton dynamics of the Fenna-Matthews-Olson (FMO) complex. In this complex, excitation energy transfer occurs between the bacteriochlorophyll a (BChl a) pigments. Two quantum mechanics/molecular mechanics (QM/MM) studies, each with a different force-field and quantum chemistry approach, reported different excitation energy distributions for the FMO complex. To understand the reasons for these differences in the predicted excitation energies, we have carried out a comparative study between the simulations using the CHARMM and AMBER force field and the Zerner intermediate neglect of differential orbital (ZINDO)/S and time-dependent density functional theory (TDDFT) quantum chemistry methods. The calculations using the CHARMM force field together with ZINDO/S or TDDFT always show a wider spread in the energy distribution compared to those using the AMBER force field. High- or low-energy tails in these energy distributions result in larger values for the spectral density at low frequencies. A detailed study on individual BChl a molecules in solution shows that without the environment, the density of states is the same for both force field sets. Including the environmental point charges, however, the excitation energy distribution gets broader and, depending on the applied methods, also asymmetric. The excitation energy distribution predicted using TDDFT together with the AMBER force field shows a symmetric, Gaussian-like distribution.