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Decompositions of Free Energies in Molecular Simulation
This thesis describes advances in methods to measure free energy changes in simulations
of molecular systems. In each case the free energy is decomposed into local environments
which reveal insights about the complex systems being studied. Free energy is a fundamental
quantity that can be used to predict whether changes in state are physically favourable.
This can be used to predict the solubility of molecules and whether molecules are likely
to bind to proteins. There are a handful of methods which measure free energy from
molecular simulations. In chapter 3 we show results for an improved endpoint free energy
method using inhomogeneous fluid solvation theory (IFST) which takes second order
fluid-fluid entropy corrections into account. This is applied to a system of Lennard-Jones
particles which show no measurable second order entropy contribution which fits with
theoretical predictions. In chapter 4 an adaptation to the Zwanzig equation for path based
exponential averaging methods is made. The equation is expanded to give contributions
associated with every atom in the system. This method is called atomwise free energy perturbation
and is applied to small molecules and ligand-protein binding. In chapter 5, IFST
is applied to decompose hydration free energy at the surface of a protein into hydration
sites. From these sites, information is inferred about the binding conformation of two
proteins GABARAP and the GABA-A receptor. In chapter 6 statistics from hydration sites
around hundreds of proteins are analysed. The distributions of free energy are shown and
discussed for hydration sites in a range of local chemical environments. Also in chapter 6,
the hydration sites decomposition method is augmented with local energy information
associated with replacing a water molecule at a hydration site with a probe. The probe
represents a ligand, and this is compared to the binding site prediction from the previous
method. Further suggestions for improvements are made
The shows and the flows: materials, markets, and innovation in the US machine tool industry, 1945–1965
Can the Communion of Saints Help the Search for Justice in Dying well (Enough), “In Abraham's Arms, Where Lazarus is Poor no Longer”?
Expanded encyclopaedias of DNA elements in the human and mouse genomes
AbstractThe human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE1 and Roadmap Epigenomics2 data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes.11Nsciescopu
Perspectives on ENCODE
The Encylopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal of developing a comprehensive map of functional elements in the human genome. These included genes, biochemical regions associated with gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) and transcript isoforms. The marks serve as sites for candidate cis-regulatory elements (cCREs) that may serve functional roles in regulating gene expression1. The project has been extended to model organisms, particularly the mouse. In the third phase of ENCODE, nearly a million and more than 300,000 cCRE annotations have been generated for human and mouse, respectively, and these have provided a valuable resource for the scientific community.11Nsciescopu