Identifying ligand binding sites and poses using GPU-accelerated Hamiltonian replica exchange molecular dynamics

We present a method to identify small molecule ligand binding sites and poses within a given protein crystal structure using GPU-accelerated Hamiltonian replica exchange molecular dynamics simulations. The Hamiltonians used vary from the physical end state of protein interacting with the ligand to an unphysical end state where the ligand does not interact with the protein. As replicas explore the space of Hamiltonians interpolating between these states, the ligand can rapidly escape local minima and explore potential binding sites. Geometric restraints keep the ligands from leaving the vicinity of the protein and an alchemical pathway designed to increase phase space overlap between intermediates ensures good mixing. Because of the rigorous statistical mechanical nature of the Hamiltonian exchange framework, we can also extract binding free energy estimates for all putative binding sites. We present results of this methodology applied to the T4 lysozyme L99A model system for three known ligands and one non-binder as a control, using an implicit solvent. We find that our methodology identifies known crystallographic binding sites consistently and accurately for the small number of ligands considered here and gives free energies consistent with experiment. We are also able to analyze the contribution of individual binding sites to the overall binding affinity. Our methodology points to near term potential applications in early-stage structure-guided drug discovery.     

Highly transparent silica monoliths embedded with high concentration oxide nanoparticles

Silica monoliths embedded with high concentration of γ-Fe₂O₃ or TiO₂ nanoparticles were prepared by a sol–gel procedure designed according to the inherent properties of oxide colloids. In the first step, highly dispersible oxide nanoparticles were produced using an in situ modification sol–gel strategy. Then, these particles were re-dispersed in silicon alkoxide-containing solution to form a stable colloidal solution. The hydrolysis and condensation reactions of alkoxide were catalyzed by an organic base (morpholine). Due to the large molecule size of morpholine, the electric double layer on the surface of colloidal particles was not compressed by the ionized morpholine molecules. The colloidal solution thus remained stable during the gelation process. Through this procedure, oxide nanoparticles could be immobilized homogeneously in the pores of a silica matrix, forming highly transparent and crack-free monoliths.     

Validity of Inorganic Nanosheets as an Efficient Planar Substituent To Enhance the Enantioselectivity of Transition‐Metal‐Catalyzed Asymmetric Synthesis

Effectively enhancing the enantioselectivity is a persistent challenge in heterogeneous asymmetric catalysis. Here, the validity of a layered double hydroxides (LDH) nanosheet as an efficient planar substituent to enhance the enantioselectivity has been investigated theoretically; first in vanadium‐catalyzed asymmetric epoxidation of allylic alcohols, and then in zinc‐catalyzed direct asymmetric aldol addition. The computational predication is further confirmed experimentally in zinc‐catalyzed direct asymmetric aldol addition by controlling the location of catalytic sites.     

Catalytic Asymmetric Construction of Quaternary α‐Amino Acid Containing Pyrrolidines through 1,3‐Dipolar Cycloaddition of Azomethine Ylides to α‐Aminoacrylates

The first catalytic enantioselective 1,3‐dipolar cycloaddition of azomethine ylides to α‐aminoacrylate catalyzed by a AgOAc/ferrocenyl oxazolinylphosphine (FOXAP) system was developed, which exhibits excellent exo‐ and enantioselectivity (92–99 % ee). This process provides efficient access to useful 4‐aminopyrrolidine‐2,4‐dicarboxylic acid (APDC)‐like compounds containing a unique quaternary α‐amino acid unit.     

Mechanism of Copper(I)‐Catalyzed Allylic Alkylation of Phosphorothioate Esters: Influence of the Leaving Group on α Regioselectivity

The mechanism of Cu^I‐catalyzed allylic alkylation and the influence of the leaving groups (OPiv, SPiv, Cl, SPO(OiPr)₂; Piv: pivavloyl) on the regioselectivity of the reaction have been explored by using density functional theory (DFT). A comprehensive comparison of many possible reaction pathways shows that [(iPr)₂Cu]^? prefers to bind first oxidatively to the double bond of the allylic substrate at the anti position with respect to the leaving group, and this is followed by dissociation of the leaving group. If the leaving group is not taken into account, the reaction then undergoes an isomerization and a reductive elimination process to give the α‐ or γ‐selective product. If OPiv, SPiv, Cl, or SPO(OiPr)₂ groups are present, the optimal route for the formation of both α‐ and γ‐substituted products changes from the stepwise elimination to the direct process, in which the leaving group plays a stabilizing role for the reactant and destabilizes the transition state. The differences to the energy barrier for the α‐ and γ‐substituted products are 2.75 kcal mol^?1 with SPO(OiPr)₂, 2.44 kcal mol^?1 with SPiv, 2.33 kcal mol^?1 with OPiv, and 1.98 kcal mol^?1 with Cl, respectively; these values show that α regioselectivity in the allylic alkylation follows a SPO(OiPr)₂>SPiv>OPiv>Cl trend, which is in satisfactory agreement with the experimental findings. This trend mainly originates in the differences between the attractive electrostatic forces and the repelling steric interactions of the SPO(OiPr)₂, SPiv, OPiv, and Cl groups on the Cu group.     

Impacts of some macromolecules on the characteristics of hydrogels prepared from pineapple peel cellulose using ionic liquid

Composite hydrogels were prepared from pineapple peel cellulose with the combinations of polyethylene glycol (PEG), polyvinyl alcohol (PVA), к-carrageenan (CN), or soluble starch (SH) in 1-allyl-3-methylimidazolium chloride solvent. Impacts of these macromolecules on the texture profile analysis (TPA) parameters, equilibrium swelling ratio (ESR), and sodium salicylate (NaSA) load of the prepared hydrogels were studied. The NaSA release kinetics of the composite hydrogels were also compared. The composite hydrogels exhibited differences in Fourier transform infrared spectroscopy (FTIR), TPA parameters, ESR, NaSA load ratio, and release kinetics. CN addition increased the hardness of the hydrogels, while PEG played an opposite role. SH and PVA could decrease hardness, gumminess, and resilience, and SH could increase the springiness and cohesiveness of the hydrogels. Most of the composite hydrogels exhibited the same basic FTIR features as the simple hydrogel. Freeze-dried composite hydrogels exhibited a markedly higher ESR than the oven-dried ones, and additions of PEG, PVA, CN, and SH showed the same effect. Addition of the PEG and PVA combination could lower the ESR of the hydrogels, whereas additions of the PEG and CN combination or PEG and SH combination could markedly increase the ESR of the hydrogels. Addition of PEG, PVA, CN, and SH respectively could increase the NaSA load ratio of the hydrogels. Oven-drying treatment, additions of the PEG and PVA combination or PEG and CN combination were propitious for extending the NaSA fast-release phase of the hydrogels.     

基于ADS-B飞行安全实时监控及半物理测试平台

针对现有飞行安全监控体系中ACARS报文航迹点数量稀疏、分布不均匀、时延长,提出基于ADS-B技术实现实时、不间断飞行安全监控。首先,建立了基于ADS-B实时飞行安全监控体系架构,对飞行过程中存在的误操作进行实时检测并告警;然后,本着实用、可靠的原则,利用现有的计算机辅助软件,建立了ADS-B实时飞行安全半物理测试平台;最后,基于该平台建立了设计实时飞行安全监控系统的工程化、规范化流程。     

Noncommutative geometry and conformal geometry. III. Vafa–Witten inequality and Poincaré duality

This paper is the third part of a series of papers whose aim is to use the framework of twisted spectral triples to study conformal geometry from a noncommutative geometric viewpoint. In this paper we reformulate the inequality of Vafa–Witten [42] in the setting of twisted spectral triples. This involves a notion of Poincaré duality for twisted spectral triples. Our main results have various consequences. In particular, we obtain a version in conformal geometry of the original inequality of Vafa–Witten, in the sense of an explicit control of the Vafa–Witten bound under conformal changes of metrics. This result has several noncommutative manifestations for conformal deformations of ordinary spectral triples, spectral triples associated with conformal weights on noncommutative tori, and spectral triples associated with duals of torsion-free discrete cocompact subgroups satisfying the Baum–Connes conjecture.