Consecutive Aromatic Residues Are Required for Improved Efficacy of β-Sheet Breakers

Alzheimer’s disease is a fatal neurodegenerative malady which up to very recently did not have approved therapy modifying its course. After controversial approval of aducanumab (monoclonal antibody clearing β-amyloid plaques) by FDA for use in very early stages of disease, possibly new avenue opened for the treatment of patients. In line with this approach is search for compounds blocking aggregation into amyloid oligomers subsequently forming fibrils or compounds helping in getting rid of plaques formed by β-amyloid fibrils. Here we present in silico work on 627 sixtapeptide β-sheet breakers (BSBs) containing consecutive three aromatic residues. Three of these BSBs caused dissociation of one or two β-amyloid chains from U-shaped β-amyloid protofibril model 2BEG after docking and subsequent molecular dynamics simulations. Thorough analysis of our results let us postulate that the first steps of binding these successful BSBs involve π–π interactions with stacked chains of F19 and later also with F20 (F3 and F4 in 2BEG model of protofibril). The consecutive location of aromatic residues in BSBs makes them more attractive for chains of stacked F3 and F4 within the 2BEG model. Spotted by us, BSBs may be prospective lead compounds for an anti-Alzheimer’s therapy.     

NMR Characterization of Long-Chain Fatty Acylcarnitine Binding to the Mitochondrial Carnitine/Acylcarnitine Carrier

The mitochondrial carnitine/acylcarnitine carrier (CAC) transports short-, medium- and long-carbon chain acylcarnitines across the mitochondrial inner membrane in exchange for carnitine. How CAC recognizes the substrates with various fatty acyl groups, especially long-chain fatty acyl groups, remains unclear. Here, using nuclear magnetic resonance (NMR) technology, we have shown that the CAC protein reconstituted into a micelle system exhibits a typical six transmembrane structure of the mitochondrial carrier family. The chemical shift perturbation patterns of different fatty acylcarnitines suggested that the segment A76–G81 in CAC specifically responds to the long-chain fatty acylcarnitine. Molecular dynamics (MD) simulations of palmitoyl-L-carnitine inside the CAC channel showed the respective interaction and motion of the long-chain acylcarnitine in CAC at the cytosol-open state and matrix-open state. Our data provided a molecular-based understanding of CAC structure and transport mechanism.     

AlphaFold2: A Role for Disordered Protein/Region Prediction?

The development of AlphaFold2 marked a paradigm-shift in the structural biology community. Herein, we assess the ability of AlphaFold2 to predict disordered regions against traditional sequence-based disorder predictors. We find that AlphaFold2 performs well at discriminating disordered regions, but also note that the disorder predictor one constructs from an AlphaFold2 structure determines accuracy. In particular, a naïve, but non-trivial assumption that residues assigned to helices, strands, and H-bond stabilized turns are likely ordered and all other residues are disordered results in a dramatic overestimation in disorder; conversely, the predicted local distance difference test (pLDDT) provides an excellent measure of residue-wise disorder. Furthermore, by employing molecular dynamics (MD) simulations, we note an interesting relationship between the pLDDT and secondary structure, that may explain our observations and suggests a broader application of the pLDDT for characterizing the local dynamics of intrinsically disordered proteins and regions (IDPs/IDRs).     

The Use of Molecular Dynamics Simulation Method to Quantitatively Evaluate the Affinity between HBV Antigen T Cell Epitope Peptides and HLA-A Molecules

Chronic hepatitis B virus (HBV), a potentially life-threatening liver disease, makes people vulnerable to serious diseases such as cancer. T lymphocytes play a crucial role in clearing HBV virus, while the pathway depends on the strong binding of T cell epitope peptide and HLA. However, the experimental identification of HLA-restricted HBV antigenic peptides is extremely time-consuming. In this study, we provide a novel prediction strategy based on structure to assess the affinity between the HBV antigenic peptide and HLA molecule. We used residue scanning, peptide docking and molecular dynamics methods to obtain the molecular docking model of HBV peptide and HLA, and then adopted the MM-GBSA method to calculate the binding affinity of the HBV peptide–HLA complex. Overall, we collected 59 structures of HLA-A from Protein Data Bank, and finally obtained 352 numerical affinity results to figure out the optimal bind choice between the HLA-A molecules and 45 HBV T cell epitope peptides. The results were highly consistent with the qualitative affinity level determined by the competitive peptide binding assay, which confirmed that our affinity prediction process based on an HLA structure is accurate and also proved that the homologous modeling strategy for HLA-A molecules in this study was reliable. Hence, our work highlights an effective way by which to predict and screen for HLA-peptide binding that would improve the treatment of HBV infection.     

Intramolecular Interaction with the E6 Region Stabilizes the Closed Conformation of the N-SH2 Domain and Concurs with the Self-Inhibitory Docking in Downregulating the Activity of the SHP2 Tyrosine Phosphatase: A Molecular Dynamics Study

The localization and activity of the SHP2 tyrosine phosphatase across different cellular compartments to the target substrates are steered by the binding of phosphotyrosine (pY) peptides to the tandem SH2 domains. The most N-terminal domain (N-SH2) can also keep the enzyme inactive by intramolecular occlusion of the catalytic site. Enzyme activity can be recovered by an allosteric disruption of this self-inhibitory docking upon the binding of pY peptides to the N-SH2 domain. Prior to this, the N-SH2 domain must abandon the closed conformation because it impedes the access of pY peptides to the binding cleft. Although it cooperates with the self-inhibitory docking in the negative regulation of the phosphatase activity, the structural determinants of the stability of the closed conformation in the self-inhibited phosphatase are still elusive. To address this issue, a molecular dynamics simulation study is carried out. It is shown that the closed conformation is stabilized by the interaction of the N-SH2 domain with a conserved peptide portion in the region encoded by PTPN11 exon 6 (E6).     

武器系统发射动力学CAD软件研究

从工程应用出发,采用多体系统动力学方法和软件工程基本理论,设计了一套武器系统发射动力学CAD分析软件,利用这一软件对武器系统发射过程进行了仿真计算,计算结果表明软件符合设计要求,可用于工程计算和设计。     

COMPLEXITY AND ERROR IN SOCIAL DYNAMICS

A model of cultural dynamics based on the work of Colin Renfrew is briefly described. It is shown how the general concepts of complexity and error pertain to this kind of cultural model. In particular, it is suggested that conflict in cultural contexts arises through the generation of diverse simple models of the culture, created by different members of the culture. We indicate how general system-theoretic concepts can thus be brought to bear on problems of conflict in and between cultures.     

引风机内颗粒沉积的数值模拟

以重整化群k-ε 模型为基础,利用计算流体力学（computation fluid dynanics,CFD）对离心式引风机的内部流场进行数值模拟。采用拉格朗日颗粒轨道模型,得到固体颗粒在引风机内的运行轨迹;加入吹灰气流,通过数值模拟验证其减少颗粒沉积的可行性。     

Life Prediction Based on Transient Dynamics Analysis of Van Semi-trailer with Air Suspension System

The early fatigue damage in the van-body of the semi-trailer is often caused by the unique mechanical characteristics and the dynamic impact of the loads.The traditional finite element method with static strength analysis cannot support the fatigue design of van-body;thus,the dynamics analysis should be adopted for the endurance performance.The accurate dynamics model to describe the transient impacts of all kinds of uneven road and the proper system transfer functions to calculate the load transfer effects...