X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists

We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X-ray crystallography to reveal the binding mode of an antagonist series to the A_2A adenosine receptor (AR). Eight A_2AAR binding site mutations from biophysical mapping experiments were initially analyzed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives. Their affinities for the A_2AAR were experimentally determined and investigated through a cycle of ligand-FEP calculations, validating the binding orientation of the different chemical substituents proposed. Subsequent X-ray crystallography of the A_2AAR with a low and a high affinity chromone derivative confirmed the predicted binding orientation. The new molecules and structures here reported were driven by free energy calculations, and provide new insights on antagonist binding to the A_2AAR, an emerging target in immuno-oncology.     

结合PBL的思维导图法在大学化学“四大平衡”教学中的应用

Taking the chemical equilibria including acid-base equilibrium, complexation equilibrium, precipitation equilibrium and redox equilibrium as an example, the application of the mind mapping combined with problem-based learning in university chemistry teaching is introduced.     

Site mapping and small molecule blind docking reveal a possible target site on the SARS-CoV-2 main protease dimer interface

The SARS-CoV-2 virus is causing COVID-19 resulting in an ongoing pandemic with serious health, social, and economic implications. Much research is focused in repurposing or identifying new small molecules which may interact with viral or host-cell molecular targets. An important SARS-CoV-2 target is the main protease (M^pro), and the peptidomimetic α-ketoamides represent prototypical experimental inhibitors. The protease is characterised by the dimerization of two monomers each which contains the catalytic dyad defined by Cys¹⁴⁵ and His⁴¹ residues (active site). Dimerization yields the functional homodimer. Here, our aim was to investigate small molecules, including lopinavir and ritonavir, α-ketoamide 13b, and ebselen, for their ability to interact with the M^pro. The sirtuin 1 agonist SRT1720 was also used in our analyses. Blind docking to each monomer individually indicated preferential binding of the ligands in the active site. Site-mapping of the dimeric protease indicated a highly reactive pocket in the dimerization region at the domain III apex. Blind docking consistently indicated a strong preference of ligand binding in domain III, away from the active site. Molecular dynamics simulations indicated that ligands docked both to the active site and in the dimerization region at the apex, formed relatively stable interactions. Overall, our findings do not obviate the superior potency with respect to inhibition of protease activity of covalently-linked inhibitors such as α-ketoamide 13b in the M^pro active site. Nevertheless, along with those from others, our findings highlight the importance of further characterisation of the M^pro active site and any potential allosteric sites.     

严格渐进伪压缩映象之修正型Mann迭代算法的强收敛性

本文利用CQ方法获得了k-严格渐进伪压缩映象修正型迭代算法的强收敛结果.此结果推广并改进了T.H.Kim和徐洪坤2006年获得的相应的一主要结果.即,从渐进非扩张映象推广到k-严格渐进伪压缩映象,并且去掉了闭凸子集C的有界性假设条件.     

A Bayesian approach to seafloor classification using multi-beam echo-sounder backscatter data

Seafloor classification using acoustic remote sensing techniques is an attractive approach due to its high-coverage capabilities and limited costs. The multi-beam echo-sounder (MBES) system provides high-resolution bathymetry and backscatter information with 100% coverage. In this paper, we present a seafloor classification method that employs the MBES backscatter data. The method uses the averaged backscatter data per beam. It, therefore, is independent on the quality of the MBES calibration. Also, its performance is insensitive to seafloor type variation along the MBES swathe and corrections for the angular dependence of the backscatter are not needed. The method accounts for the ping-to-ping variability of the backscatter intensity. It estimates both the number of seafloor types present in the survey area and the probability density function for the backscatter strength at a certain angle for each of the seafloor types. Application of the method to MBES backscatter data acquired in a well-known test area in the North Sea shows very good agreement with available ground truth. The method’s discriminatory performance for this area is demonstrated to be comparable to that of taking samples of the sediment. All seafloor types known to be present in the area are resolved for. Application of the method to the Stanton bank data set shows clearly separable areas that differ in seafloor composition.     

A study of gridless method with dynamic clouds of points for solving unsteady CFD problems in aerodynamics

When solving unsteady computational fluid dynamics problems in aerodynamics with a gridless method, a cloud of points is usually required to be regenerated due to its accommodation to moving boundaries. In order to handle this problem conveniently, a fast dynamic cloud method based on Delaunay graph mapping strategy is proposed in this paper. A dynamic cloud method makes use of algebraic mapping principles and therefore points can be accurately redistributed in the flow field without any iteration. In this way, the structure of the gridless clouds is not necessarily changed so that the clouds regeneration can be avoided successfully. The spatial derivatives of the mathematical modeling of the flow are directly determined by using weighted least‐squares method in each cloud of points, and then numerical fluxes can be obtained. A dual time‐stepping method is further implemented to advance the two‐dimensional Euler equations in arbitrary Lagarangian–Eulerian formulation in time. Finally, unsteady transonic flows over two different oscillating airfoils are simulated with the above method and results obtained are in good agreement with the experimental data. Copyright © 2009 John Wiley & Sons, Ltd.     

APPROXIMATING COMMON FIXED POINTS OF NEARLY ASYMPTOTICALLY NONEXPANSIVE MAPPINGS

We use an iteration scheme to approximate common fixed points of nearly asymptotically nonexpansive mappings.We generalize corresponding theorems of [1] to the case of two nearly asymptotically nonexpansive mappings and those of [9] not only to a larger class of mappings but also with better rate of convergence.     

Target extraction from blurred trace infrared images with a superstring galaxy template algorithm

Accurate and efficient targets extraction from blurred trace infrared images has very important meaning for latent trace evidence collection in crime scene. Based on the superstring theory, a superstring galaxy template extraction algorithm for infrared trace target is presented. First, all of the pixels are divided into three classes: target pixels, background pixels and blurred pixels. Next, the superstring template characteristics for every pixel in a blurred infrared image are calculated as the features of each pixel. Finally, a galaxy covering algorithm is proposed, target pixels and background pixels are used for training the galaxy covering domain of every galaxy classifiers, and these classifiers will divide each blurred pixel into two classes: a target pixel or a background pixel. Experimental results indicate that the superstring galaxy template algorithm can improve the target extraction rate and reduce the extraction error rate.     

图胞映射的一种改进方法

通过引入新的概念，提出了图胞映射动力系统中瞬态胞的新的分类方法，基于新的分类方法研究了动力系统中不变流形的胞映射逼近问题；并结合计算机的计算速度与内存特点，建立了完成上述压缩分类的有效算法.通过对典型算例Henon映射的应用分析，证实了该方法的有效性.