Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations

Inhibition of p53-MDM2/MDMX interaction is considered to be a promising strategy for anticancer drug design to activate wild-type p53 in tumors. We carry out molecular dynamics (MD) simulations to study the binding mechanisms of peptide and non-peptide inhibitors to MDM2/MDMX. The rank of binding free energies calculated by molecular mechanics generalized Born surface area (MM-GBSA) method agrees with one of the experimental values. The results suggest that van der Waals energy drives two kinds of inhibitors to MDM2/MDMX. We also find that the peptide inhibitors can produce more interaction contacts with MDM2/MDMX than the non-peptide inhibitors. Binding mode predictions based on the inhibitor-residue interactions show that the π–π, CH–π and CH–CH interactions dominated by shape complimentarity, govern the binding of the inhibitors in the hydrophobic cleft of MDM2/MDMX. Our studies confirm the residue Tyr99 in MDMX can generate a steric clash with the inhibitors due to energy and structure. This finding may theoretically provide help to develop potent dual-specific or MDMX inhibitors

Insights into the regulation of human CNV-miRNAs from the view of their target genes

Abstract Background microRNAs (miRNAs) represent a class of small (typically 22 nucleotides in length) non-coding RNAs that can degrade their target mRNAs or block their translation. Recent research showed that copy number alterations of miRNAs and their target genes are highly prevalent in cancers; however, the evolutionary and biological functions of naturally existing copy number variable miRNAs (CNV-miRNAs) among individuals have not been studied extensively throughout the genome. Results In this study, we comprehensively analyzed the properties of genes regulated by CNV-miRNAs, and found that CNV-miRNAs tend to target a higher average number of genes and prefer to synergistically regulate the same genes; further, the targets of CNV-miRNAs tend to have higher variability of expression within and between populations. Finally, we found the targets of CNV-miRNAs are more likely to be differentially expressed among tissues and developmental stages, and participate in a wide range of cellular responses. Conclusions Our analyses of CNV-miRNAs provide new insights into the impact of copy number variations on miRNA-mediated post-transcriptional networks. The deeper interpretation of patterns of gene expression variation and the functional characterization of CNV-miRNAs will help to broaden the current understanding of the molecular basis of human phenotypic diversity.</p

Characterizing Sprawl Development in Urban China: A Perspective from Urban Amenity

Urban sprawl in China presents unique characteristics that differ from those commonly studied in Western contexts, an aspect not fully explored in previous studies. Therefore, taking Wuhan, Hubei as an example and integrating population data, remote sensing data, and POI data, this research offers a perspective on sprawl development in urban China. By incorporating population, urban land use, and urban amenities, this study measures their dynamics to classify urban spaces and employs spatial regression models to identify the characteristics of sprawl development with spatial effects controlled. It further applies geographically weighted regression to examine the underlying spatial heterogeneity. The findings indicate that population growth and urban land expansion do not align perfectly, and further exploration identifies the various trends of sprawl development in urban core and periphery areas. On the other hand, some suburban areas show compact development trends, but the growth of local amenities may be limited due to the historical sprawl development legacies. Regression results reveal specific characteristics of this sprawl development. Key findings include the following: (1) shaped by the triple process of sprawl development of urban renewal, suburbanization, and rural revitalization, Wuhan shows a significant core-periphery structure with the trend of polycentricity; (2) overcrowding in central urban districts is the primary driver of sprawl development; (3) most traditional suburbs in Wuhan have emerged as a consequence of rapid urbanization with a legacy of sprawl development; (4) spatial heterogeneity across urban spaces highlights the necessity for locally tailored approaches to regulating sprawl development

The Potential of Latent Class Analysis: the Czech Television Audience Case Study

The thesis "The Potential of Latent Class Analysis: the Czech Television Audience Case Study" deals with latent class analysis and it's potential as a segmentation method. Three different approaches are examined - latent class analysis for joint data from six research waves, simultaneous latent class analysis for each wave separately and latent class analysis for joint data transferred into dichotomous form. The results of all three methods are compared through secondary analysis of data from case study focused on audience's perception of the Czech Television; their strong and weak points are described and the most suitable solution is chosen. Based on these findings, four identified segments of the audience are then interpreted from the point of their characteristic features and sociodemographic parameters. This paper is supported by works of classic authors in the area of latent class analysis; the thesis refers to their findings that also served as basis for composition of the research hypotheses

Integrating Multiple Accelerated Molecular Dynamics To Improve Accuracy of Free Energy Calculations

Accelerated Molecular Dynamics (aMD) is a promising enhanced sampling method to explore the conformational space of biomolecules. However, the large statistical noise in reweighting limits its accuracy to recover the original free energy profile. In this work, we propose an Integrated accelerated Molecule Dynamics (IaMD) method by integrating a series of aMD subterms with different acceleration parameters to improve the sampling efficiency and maintain the reweighting accuracy simultaneously. We use Alanine Dipeptide and three fast-folded proteins (Chignolin, Trp-cage, and Villin Headpiece) as the test objects to compare our IaMD method with aMD systematically. These case studies indicate that the statistical noise of IaMD in reweighting for free energy profiles is much smaller than that of aMD at the same level of acceleration and simulation time. To achieve the same accuracy as IaMD, aMD requires 1-3 orders of magnitude longer simulation time, depending on the complexity of the simulated system and the level of acceleration. Our method also outperforms aMD in controlling systematic error caused by the disappearance of the low-energy conformations when high acceleration parameters are used in alVID simulations for fast-folded proteins. Furthermore, the performance comparison between IaMD and the Integrated Tempering Sampling (ITS) in the case of Alanine Dipeptide demonstrates that IaMD possesses a better ability to control the potential energy region of sampling

RYBP Inhibits Progression and Metastasis of Lung Cancer by Suppressing EGFR Signaling and Epithelial-Mesenchymal Transition

Lung cancer (LC) is a common lethal malignancy with rapid progression and metastasis, and Ring1 and YY1 binding protein (RYBP) has been shown to suppress cell growth in human cancers. This study aimed to investigate the role of RYBP in LC progression and metastasis. In this study, a total of 149 LC patients were recruited, and the clinical stage of their tumors, metastasis status, survival time, presence of epidermal growth factor receptor (EGFR) mutation, and RYBP expression levels were measured. RYBP silencing and overexpression were experimentally performed in LC cell lines and in nude mice, and the expressions of genes in EGFR-related signaling pathways and epithelial-mesenchymal transition (EMT) were detected. The results showed that RYBP was downregulated in LC compared with adjacent normal tissues, and low RYBP expression was associated with a more severe clinical stage, high mortality, high metastasis risk, and poor survival. Cell proliferation and xenograft growth were inhibited by RYBP overexpression, whereas proliferation and xenograft growth were accelerated by RYBP silencing. EGFR and phosphorylated-EGFR levels were upregulated when RYBP was silenced, whereas EGFR, p-EGFR, p-AKT, and p-ERK were downregulated when RYBP was overexpressed. Low RYBP expression was related to a high metastasis risk, and metastasized tumors showed low RYBP levels. Cell migration and invasion were promoted by silencing RYBP but were inhibited by overexpressed RYBP. In addition, the EMT marker vimentin showed diminished expression, and E-cadherin was promoted by the overexpression of RYBP. In conclusion, our data suggest that RYBP suppresses cell proliferation and LC progression by impeding the EGFR-ERK and EGFR-AKT signaling pathways and thereby inhibiting cell migration and invasion and LC metastasis through the suppression of EMT

Accurate Evaluation of Ion Conductivity of the Gramicidin A Channel Using a Polarizable Force Field without Any Corrections

Classical molecular dynamic (MD) simulation of membrane proteins faces significant challenges in accurately reproducing and predicting experimental observables such as ion conductance and permeability due to its incapability of precisely describing the electronic interactions in heterogeneous systems. In this work, the free energy profiles of K+ and Na+ permeating through the gramicidin A channel are Characterized by using the AMOEBA polarizable force field with a total sampling time of 1 mu s. Our results indicated that by explicitly introducing the multipole terms and polarization into the electrostatic potentials, the permeation free energy barrier of K+ through the gA channel is considerably reduced compared to the overestimated results obtained from the fixed-charge model. Moreover; the estimated maximum conductance, without any corrections, for both K+ and Na+ passing through the gA channel are much closet to the experimental results than any classical MD simulations, demonstrating the power of AMOEBA in investigating the membrane proteins

Optimal Sizing of Seawater Pumped Storage Plant with Variable-Speed Units Considering Offshore Wind Power Accommodation

To improve the output characteristics of offshore wind power and to enhance the wind power accommodation, this paper analyzes its output characteristics along the southern coast in China, and then proposes an optimal sizing method of seawater pumped storage plant (SPSP) with variable-speed units in a connected mode on an islanded microgrid. Based on the constraints of variable-speed unit characteristics and power smoothness at the point of common coupling (PCC), the maximum static revenue as the objective function for the optimal sizing of SPSP is established. Notably, under an appropriate smoothness rate at PCC, the constraints that are mentioned above can adequately reflect the advantages of variable-speed units: fast power response and wide operating range. Additionally, they contain more concise models and variables than previously, which are friendly for optimizing the calculations. The results demonstrate that the proposed method is feasible and practical, by simulating and comparing in different scenarios

Coarse-Grained Modeling of Nucleic Acids Using Anisotropic Gay–Berne and Electric Multipole Potentials

In this work, we attempt to apply a coarse-grained (CG) model, which is based on anisotropic Gay–Berne and electric multipole (EMP) potentials, to the modeling of nucleic acids. First, a comparison has been made between the CG and atomistic models (AMBER point-charge model) in the modeling of DNA and RNA hairpin structures. The CG results have demonstrated a good quality in maintaining the nucleic acid hairpin structures, in reproducing the dynamics of backbone atoms of nucleic acids, and in describing the hydrogen-bonding interactions between nucleic acid base pairs. Second, the CG and atomistic AMBER models yield comparable results in modeling double-stranded DNA and RNA molecules. It is encouraging that our CG model is capable of reproducing many elastic features of nucleic acid base pairs in terms of the distributions of the interbase pair step parameters (such as shift, slide, tilt, and twist) and the intrabase pair parameters (such as buckle, propeller, shear, and stretch). Finally, The GBEMP model has shown a promising ability to predict the melting temperatures of DNA duplexes with different lengths