Coarse-Grained Free-Energy Simulations of Conformational State Transitions in an Adenosine 5′-Triphosphate-binding Cassette Exporter

ATP-binding cassette exporters transport many substrates out of cellular membranes via alternating between inward-facing and outward-facing conformations. Despite extensive research efforts over the past decades, understanding of the molecular mechanism remains elusive. As these large-scale conformational movements are global and collective, we have previously performed extensive coarse-grained molecular dynamics simulations of the potential of mean force along the conformational transition pathway [J. Phys. Chem. B 119, 1295(2015)]. However, the occluded conformational state, in which both the internal and external gate are closed, was not determined in the calculated free energy profile. In this work, we extend the above methods to the calculation of the free energy profile along the reaction coordinate, d1-d2, which are the COM distances between the two sides of the internal(d1)and the external gate(d2). The potential of mean force is thus obtained to identify the transition pathway, along which several outward-facing, inward-facing, and occluded state structures are predicted in good agreement with structural experiments. Our coarse-grained molecular dynamics free-energy simulations demonstrate that the internal gate is closed before the external gate is open during the inward-facing to outward-facing transition and vice versa during the inward-facing to outward-facing transition. Our results capture the unidirectional feature of substrate translocation via the exporter, which is functionally important in biology. This finding is different from the previous result, in which both the internal and external gates are open reported in an X-ray experiment [Proc. Natl. Acad. Sci. USA 104,19005(2007)]. Our study sheds light on the molecular mechanism of the state transitions in an ATP-binding cassette exporter.

Hypothesis of the osthol intervention in osteoarthritis treatment through COX-2 specific pathway

Osteoarthritis(OA)is a joint degenerative disease characterized by softening and peeling of articular cartilage,reactive hyperplasia of subchondral bone,and narrowing of joint space,which seriously affects the quality of daily life of patients.Drug therapy is one of the effective means to treat osteoarthritis,it mainly includes the use of nonsteroidal antiinflammatory drugs,hormones and painkillers.These methods have a certain effect on alleviating symptoms,but there are also some obvious adverse reactions,and are not easy to take for a long time.Osthol is a natural coumarin isolated from Pinaceae plants.It has pharmacological effects such as anti-inflammatory,antioxidant and neuroprotective.A large number of studies and experiments show that Osthol has a good effect in the treatment of osteoarthritis,and no obvious harmful effect has been found.Therefore,by analyzing and sorting out the relevant experiments and literatures published in recent years,this paper puts forward some scientific hypotheses on the possible specific ways of regulating COX-2 mRNA expression,one of the important roles of Osthol in the treatment of osteoarthritis,in order to clarify the possible potential mechanism and inspire subsequent related research.

Ultra-compact lithium niobate microcavity electro-optic modulator beyond 110 GHz

A lithium-niobate-on-insulator(LNOI)electro-optic(EO)modulator based on a 2×2 FP-cavity was designed and realized with an ultra-compact footprint and an ultra-high bandwidth.A comprehensive analysis on the present LNOI FP-cavity modulator was conducted to reveal the dependence of modulation bandwidth and modulation effi-ciency on the cavity Q-factor and the operation wavelength detuning to the resonance.In particular,the 2×2 FP cavity was designed to achieve an optimal Q factor by reducing the reflectivity of reflectors and the cavity length,thus reducing the photon lifetime in the cavity.An ultra-short effective cavity length of only∼50μm was achieved for the designed LNOI FP-cavity modulator,with itsfootprint being as compact as∼4×500μm 2.It was demonstrated theoretically that the modulation bandwidth could be improved significantly to be over 200 GHz by utilizing the peaking enhancement effect.The fabricated device exhibited an excess loss of∼1 dB and an extinction ratio of∼20 dB in experiments,while the measured 3-dB bandwidth was higher than 110 GHz(beyond the maximal range of the facilities in experiments).Up till now,to our best knowledge,this has been the first LNOI microcavity modulator with a bandwidth higher than 110 GHz.Finally,high-quality eye-diagrams of 100 Gbps on-off keying(OOK)and 140 Gbps 4-pulse amplitude modulation(PAM4)signals were demonstrated experimentally,and the energy consumption for the OOK signals was as low as 4.5 fJ/bit.