Molecular Dynamics Simulations of Enzymes with Quantum Mechanical/Molecular Mechanical Potentials

S-adenosyl methionine (SAM) dependent methylation process is universally found in all branches of life. It has important implications in mammalian pathogenesis and plant metabolism. The methyl transfer is normally catalyzed by SAM-dependent methyltransferases(MTases). Two MTases are studied in this dissertation: the 1,7-dimethylxanthine methyltransferase (DXMT) which involve in plant caffeine biosynthesis, and the protein arginine methyltransferase 5(PRMT5) that participates in eukaryotic posttranslational modification. The late phase of caffeine biosynthesis starts from the substrate xanthosine and ends with the product caffeine, with theobromine as an intermediate product. DXMT is a key enzyme in this process and catalyzes two methylation steps: 1)methylation of 7-methylxanthine to form theobromine; 2)methylation of theobromine to form caffeine. The catalytic mechanism and product promiscuity of DXMT is intriguing. In Chapter 1, the quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) and free energy simulations were performed to explain the dual catalytic roles of DXMT. Simulation results show that a histidine residue may act as a general base catalyst during methylations. PRMTs can work as modifiers for histones and methylate the substrate arginine, thus interfering with histone code orchestration. The product specificity of PRMTs refers to their ability to produce either symmetric di-methylarginine(SDMA), asymmetric di-methylarginine(ADMA) or mono-methylarginine(MMA). Understanding the product specificity of PRMTs is important since different methylations may cause distinctive, even inverse biological consequences. PRMT5 produces SDMA, as compared to PRMT1 and PRMT3 that produce ADMA. In Chapter 2, simulations of PRMT5 have drawn a theoretical insight into the catalytic difference between SDMA and ADMA. Neddylation is a type of eukaryotic Ubiquitin-like (UBL) protein modification that is essential in cell division and development. Unlike ubiquitin and other small ubiquitin-like modifiers which target variety of protein substrates, the UBL NEDD8 is highly selective on modifying cullin proteins and contributes to 10% ~20% of all cellular ubiquitination and ubiquitination-like modification. In Chapter 3, the crystal structure of a trapped E3-E2 ̴ NEDD8-CUL1 intermediate was used for modeling, and simulations were applied to investigate the catalytic mechanism of NEDD8 transfer from E2 to the substrate. Some important insights were observed that may be used to understand the functional properties of the enzyme

Supervised Sparsity Preserving Projections for Face Recognition

Recently feature extraction methods have commonly been used as a principled approach to understand the intrinsic structure hidden in high-dimensional data. In this paper, a novel supervised learning method, called Supervised Sparsity Preserving Projections (SSPP), is proposed. SSPP attempts to preserve the sparse representation structure of the data when identifying an efficient discriminant subspace. First, SSPP creates a concatenated dictionary by class-wise PCA decompositions and learns the sparse representation structure of each sample under the constructed dictionary using the least squares method. Second, by maximizing the ratio of non-local scatter to local scatter, a Laplacian discriminant function is defined to characterize the separability of the samples in the different sub-manifolds. Then, to achieve improved recognition results, SSPP integrates the learned sparse representation structure as a regular term into the Laplacian discriminant function. Finally, the proposed method is converted into a generalized eigenvalue problem. The extensive and promising experimental results on several popular face databases validate the feasibility and effectiveness of the proposed approach

Survey of Computational Algorithms for MicroRNA Target Prediction

MicroRNAs (miRNAs) are 19 to 25 nucleotides non-coding RNAs known to possess important post-transcriptional regulatory functions. Identifying targeting genes that miRNAs regulate are important for understanding their specific biological functions. Usually, miRNAs down-regulate target genes through binding to the complementary sites in the 3' untranslated region (UTR) of the targets. In part, due to the large number of miRNAs and potential targets, an experimental based prediction design would be extremely laborious and economically unfavorable. However, since the bindings of the animal miRNAs are not a perfect one-to-one match with the complementary sites of their targets, it is difficult to predict targets of animal miRNAs by accessing their alignment to the 3' UTRs of potential targets. Consequently, sophisticated computational approaches for miRNA target prediction are being considered as essential methods in miRNA research

Research Issues, Challenges, and Opportunities of Wireless Power Transfer-Aided Full-Duplex Relay Systems

We present a comprehensive review for wireless power transfer (WPT)-aided full-duplex (FD) relay systems. Two critical challenges in implementing WPT-aided FD relay systems are presented, that is, pseudo FD realization and high power consumption. Existing time-splitting or power-splitting structure based-WPT-aided FD relay systems can only realize FD operation in one of the time slots or only forward part of the received signal to the destination, belonging to pseudo FD realization. Besides, self-interference is treated as noise and self-interference cancellation (SIC) operation incurs high power consumption at the FD relay node. To this end, a promising solution is outlined to address the two challenges, which realizes consecutive FD realization at all times and forwards all the desired signal to the destination for decoding. Also, active SIC, that is, analog/digital cancellation, is not required by the proposed solution, which effectively reduces the circuit complexity and releases high power consumption at the FD relay node. Specific classifications and performance metrics of WPT-aided FD relay systems are summarized. Some future research is also envisaged for WPT-aided FD systems

From heart failure and kidney dysfunction to cardiorenal syndrome: TMAO may be a bridge

The study of trimethylamine oxide (TMAO), a metabolite of gut microbiota, and heart failure and chronic kidney disease has made preliminary achievements and been summarized by many researchers, but its research in the field of cardiorenal syndrome is just beginning. TMAO is derived from the trimethylamine (TMA) that is produced by the gut microbiota after consumption of carnitine and choline and is then transformed by flavin-containing monooxygenase (FMO) in the liver. Numerous research results have shown that TMAO not only participates in the pathophysiological progression of heart and renal diseases but also significantly affects outcomes in chronic heart failure (CHF) and chronic kidney disease (CKD), besides influencing the general health of populations. Elevated circulating TMAO levels are associated with adverse cardiovascular events such as HF, myocardial infarction, and stroke, patients with CKD have a poor prognosis as well. However, no study has confirmed an association between TMAO and cardiorenal syndrome (CRS). As a syndrome in which heart and kidney diseases intersect, CRS is often overlooked by clinicians. Here, we summarize the research on TMAO in HF and kidney disease and review the existing biomarkers of CRS. At the same time, we introduced the relationship between exercise and gut microbiota, and appropriately explored the possible mechanisms by which exercise affects gut microbiota. Finally, we discuss whether TMAO can serve as a biomarker of CRS, with the aim of providing new strategies for the detection, prognostic, and treatment evaluation of CRS