Recurring side-chain triads in monomeric enzymatic structures

An algorithm was developed to exhaustively screen monomeric enzymatic structures for recurring 3-residue side-chain arrangements. The algorithm was used in the screening of two datasets: 100 enzymatic structures with a recurring 3-residue active site, and 100 enzymatic structures with a unique 3-residue active site. In each structure, the algorithm considered all distinct side-chain triads that can be compiled from the entire complement of residues in a single isolated chain. Increasing chain length demonstrated a logarithmic growth in the number of recurring triads. The distribution of total distances in recurring triads adhered to normality while the distribution of unique triad distances appeared negatively skewed. Analysis of variance indicated that the means of maximum and average total distances are significantly greater in unique triads than in recurring triads. Screening for recurring triads in synthetically generated alternative rotamer structures demonstrated an overall decrease in the percent of recurring triads, as compared to the natural structures

Systems Chemistry and Parrondo’s Paradox: Computational Models of Thermal Cycling

A mathematical concept known as Parrondo’s paradox motivated the development of several novel computational models of chemical systems in which thermal cycling was explored. In these kinetics systems we compared the rates of formation of product under cycling temperature and steady-sate conditions. We found that a greater concentration of product was predicted under oscillating temperature conditions. Our computational models of thermal cycling suggest new applications in chemical and chemical engineering systems

An optical model for an analogy of Parrondo game and designing Brownian ratchets

An optical model of classical photons propagating through array of many beam splitters is developed to give a physical analogy of Parrondo's game and Parrondo-Harmer-Abbott game. We showed both the two games are reasonable game without so-called game paradox and they are essentially the same. We designed the games with long-term memory on loop lattice and history-entangled game. The strong correlation between nearest two rounds of game can make the combination of two losing game win, lose or oscillate between win and loss. The periodic potential in Brownian ratchet is analogous to a long chain of beam splitters. The coupling between two neighboring potential wells is equivalent to two coupled beam splitters. This correspondence may help us to understand the anomalous motion of exceptional Brownian particles moving in the opposite direction to the majority. We designed the capital wave for a game by introducing correlations into independent capitals instead of sub-games. Playing entangled quantum states in many coupled classical games obey the same rules for manipulating quantum states in many body physics.Comment: 18 pages in two colum

Comprehensive and unbiased multiparameter high-throughput screening by compaRe finds effective and subtle drug responses in AML models

Large-scale multiparameter screening has become increasingly feasible and straightforward to perform thanks to developments in technologies such as high-content microscopy and high-throughput flow cytometry. The automated toolkits for analyzing similarities and differences between large numbers of tested conditions have not kept pace with these technological developments. Thus, effective analysis of multiparameter screening datasets becomes a bottleneck and a limiting factor in unbiased interpretation of results. Here we introduce compaRe, a toolkit for large-scale multiparameter data analysis, which integrates quality control, data bias correction, and data visualization methods with a mass-aware gridding algorithm-based similarity analysis providing a much faster and more robust analyses than existing methods. Using mass and flow cytometry data from acute myeloid leukemia and myelodysplastic syndrome patients, we show that compaRe can reveal interpatient heterogeneity and recognizable phenotypic profiles. By applying compaRe to high-throughput flow cytometry drug response data in AML models, we robustly identified multiple types of both deep and subtle phenotypic response patterns, highlighting how this analysis could be used for therapeutic discoveries. In conclusion, compaRe is a toolkit that uniquely allows for automated, rapid, and precise comparisons of large-scale multiparameter datasets, including high-throughput screens.Peer reviewe

Crystal Structure of a Charge Engineered Human Lysozyme Having Enhanced Bactericidal Activity

Human lysozyme is a key component of the innate immune system, and recombinant forms of the enzyme represent promising leads in the search for therapeutic agents able to treat drug-resistant infections. The wild type protein, however, fails to participate effectively in clearance of certain infections due to inherent functional limitations. For example, wild type lysozymes are subject to electrostatic sequestration and inactivation by anionic biopolymers in the infected airway. A charge engineered variant of human lysozyme has recently been shown to possess improved antibacterial activity in the presence of disease associated inhibitory molecules. Here, the 2.04 Å crystal structure of this variant is presented along with an analysis that provides molecular level insights into the origins of the protein's enhanced performance. The charge engineered variant's two mutated amino acids exhibit stabilizing interactions with adjacent native residues, and from a global perspective, the mutations cause no gross structural perturbations or loss of stability. Importantly, the two substitutions dramatically expand the negative electrostatic potential that, in the wild type enzyme, is restricted to a small region near the catalytic residues. The net result is a reduction in the overall strength of the engineered enzyme's electrostatic potential field, and it appears that the specific nature of this remodeled field underlies the variant's reduced susceptibility to inhibition by anionic biopolymers

hESC-based human glial chimeric mice reveal glial differentiation defects in Huntington disease

Huntington’s disease (HD) is characterized by hypomyelination as well as neuronal loss. To assess the basis for myelin loss in HD, we generated bipotential glial progenitor cells (GPCs) from human embryonic stem cells (hESCs), derived from huntingtin (mHTT)-mutant embryos or normal controls, and performed RNAseq to assess mHTT-dependent changes in gene expression. In hGPCs derived from 3 mHTT hESC lines, transcription factors associated with glial differentiation and myelin synthesis were sharply down-regulated relative to normal hESC GPCs; NKX2.2, OLIG2, SOX10, MYRF and their downstream targets were all suppressed. Accordingly, when mHTT hGPCs were transplanted into hypomyelinated shiverer mice, the resultant glial chimeras were hypomyelinated; this defect could be rescued by forced expression of SOX10 and MYRF by mHTT hGPCs. The mHTT hGPCs also manifested impaired astrocytic differentiation, and developed abnormal fiber architecture. White matter involution in HD is thus a product of the cell autonomous, mHTT-dependent suppression of glial differentiation