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Self-assembly provides an attractive route to functional organic materials, with properties and hence performance depending sensitively on the organization of the molecular building blocks (1-5). Molecular organization is a direct consequence of the pathways involved in the supramolecular assembly process, which is more amenable to detailed study when using one-dimensional systems. In the case of protein fibrils, formation and growth have been attributed to complex aggregation pathways (6-8) that go beyond traditional concepts of homogeneous (9-11) and secondary (12-14) nucleation events. The self-assembly of synthetic supramolecular polymers has also been studied and even modulated (15-18), but our quantitative understanding of the processes involved remains limited. Here we report time-resolved observations of the formation of supramolecular polymers from π-conjugated oligomers. Our kinetic experiments show the presence of a kinetically favoured metastable assembly that forms quickly but then transforms into the thermodynamically favoured form. Quantitative insight into the kinetic experiments was obtained from kinetic model calculations, which revealed two parallel and competing pathways leading to assemblies with opposite helicity. These insights prompt us to use a chiral tartaric acid as an auxiliary to change the thermodynamic preference of the assembly process (19). We find that we can force aggregation completely down the kinetically favoured pathway so that, on removal of the auxiliary, we obtain only metastable assemblies., The π-conjugated oligomer S-chiral oligo(p-phenylenevinylene) (SOPV, Fig 1a) serves as a functional material in a variety of organic electronic devices, with performance critically dependent on the material's morphology (20). This [...]

The transduction function for ADP stimulation of mltochondrial ATP synthesis in skeletal muscle was reconstructed in vivo and in silico to investigate the magnitude and origin of mitochondrial sensitivity to cytoplasmic ADP concentration changes. Dynamic in vivo measurements of human leg muscle phosphocreatine (PCr) content during metabolic recovery from contractions were performed by [sup.31]P-NMR spectroscopy. The cytoplasmic ADP concentration ([ADP]) and rate of oxidative ATP synthesis (Jp) at each time point were calculated from creatine kinase equilibrium and the derivative of a monoexponential fit to the PCr recovery data, respectively. Reconstructed [ADP]-Jp relations for individual muscles containing more than 100 data points were kinetically characterized by nonlinear curve fitting yielding an apparent kinetic order and ADP affinity of 1.9 [+ or -] 0.2 and 0.022 [+ or -] 0.003 mM, respectively (means [+ or -] SD; n = 6). Next, in silico [ADP]-Jp relations for skeletal muscle were generated using a computational model of muscle oxidative ATP metabolism whereby model parameters corresponding to mitochondrial enzymes were randomly changed by 50-150% to determine control of mitochondrial ADP sensitivity. The multiparametric sensitivity analysis showed that mitochondrial ADP ultrasensitivity is an emergent property of the integrated mitochondrial enzyme network controlled primarily by kinetic properties of the adenine nucleotide translocator. mitochondria; nuclear magnetic resonance; mathematical modeling; regulation; adenosine 5'-diphosphate

A step-wise noncovalent synthetic procedure involving a preassembly step in chloroform is used to obtain dendrimer-based guest-host assemblies in water. The concepts of stepwise noncovalent synthesis have provided valuable tools for obtaining new supramolecular assemblies.

The switching taking place from S- to R-selectivity in the Candida antarctica lipase B-catalyzed ring-opening of [omega]-methylated lactones demonstrates the differences found in their rate of reaction and enantioselectivity. The S-selectivity of the ring opening is found to be low to moderate, where as the R-selectivity is always supposed to be extremely high.

Atrial fibrillation, a common cardiac arrhythmia, is promoted by atrial dilatation. Acute atrial dilatation may play a role in atrial arrhythmogenesis through mechanoelectric feedback. In experimental studies, conduction slowing and block have been observed in acutely dilated atria. In the present study, the influence of the stretch-activated current ([I.sub.sac]) on impulse propagation is investigated by means of computer simulations. Homogeneous and inhomogeneous atrial tissues are modeled by cardiac fibers composed of segments that are electrically and mechanically coupled. Active force is related to free [Ca.sup.2+] concentration and sarcomere length. Simulations of homogeneous and inhomogeneous cardiac fibers have been performed to quantify the relation between conduction velocity and [I.sub.sac] under stretch. In our model, conduction slowing and block are related to the amount of stretch and are enhanced by contraction of early-activated segments. Conduction block can be unidirectional in an inhomogeneous fiber and is promoted by a shorter stimulation interval. Slowing of conduction is explained by inactivation of [Na.sup.+] channels and a lower maximum upstroke velocity due to a depolarized resting membrane potential. Conduction block at shorter stimulation intervals is explained by a longer effective refractory period under stretch. Our observations are in agreement with experimental results and explain the large differences in intra-atrial conduction, as well as the increased inducibility of atrial fibrillation in acutely dilated atria. atrial fibrillation; excitation-contraction coupling; impulse propagation; stretch-activated current doi:10.1152/ajpheart.00923.2006

Atrial fibrillation is the most common cardiac arrhythmia. Structural cardiac defects such as fibrosis and gap junction remodeling lead to a reduced cellular electrical coupling and are known to promote atrial fibrillation. It has been observed that the expression of the hyperpolarization-activated current [I.sub.f] is increased under pathological conditions. Recent experimental data indicate a possible contribution of If to arrhythmogenesis. In this paper, the role of [I.sub.f] in action potential propagation in normal and in pathological tissue is investigated by means of computer simulations. The effect of diffuse fibrosis and gap junction remodeling is simulated by reducing cellular coupling nonuniformly. As expected, the conduction velocity decreases when cellular coupling is reduced. In the presence of [I.sub.f] the conduction velocity increases both in normal and in pathological tissue. In our simulations, ectopic activity is present in regions with high expression of If and is facilitated by cellular uncoupling. We conclude that an increased [I.sub.f] may facilitate propagation of the action potential. Hence, [I.sub.f] may prevent conduction slowing and block. Overexpression of [I.sub.f] may lead to ectopic activity, especially when cellular coupling is reduced under pathologicai conditions. Index Terms--Atrial fibrillation, bidomain model, ectopic activity, fibrosis, gap junction remodeling, hyperpolarization-activated inward current.

Recently we predicted the 3D structure of the human [beta]2-adrenergic receptor ([beta]2AR) and of the binding site of several agonists and antagonists to [beta]2AR. These predictions (MembStruk and HierDock) included no explicit water and only a few lipid molecules. Here we include explicit [H.sub.2]O and an infinite lipid bilayer membrane in molecular dynamics (MD) simulations of three systems: apo-[beta]2AR, epinephrine-bound [beta]2AR, and butoxamine-bound [beta]2AR (epinephrine is an endogenous agonist, and butoxamine is a [beta]2AR selective antagonist). The predicted structures for apo-[beta]2AR and butoxamine-[beta]2AR are stable in MD, but in epinephrine-[beta]2AR, extracellular water trickles into the binding pocket to mediate hydrogen bonding between the catechol of epinephrine and Ser-204 on helix 5. The epinephrine-[beta]2AR structure shows dynamic flexibility with small, piston-like movements of helices 3 and 6 and transient interhelical hydrogen bonding between Ser-165 on transmembrane 4 and Ser-207 on transmembrane 5. These couplings and motions may play a role in protein activation. The apo-[beta]2AR shows less dynamic flexibility, whereas the antagonist-[beta]2AR structure is quite rigid. This MD validation of the structure predictions for G protein-coupled receptors in explicit lipid and water suggests that these methods can be trusted for studying the mechanism of activation and the design of subtype-specific agonists and antagonists.