Browsing by Subject "Simulation and Modeling"

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    Conformational Changes in Two Inter-Helical Loops of Mhp1 Membrane Transporter
    (PLOS, 2015-07-17) Song, Hyun Deok; Zhu, Fangqiang; Department of Physics, School of Science
    Mhp1 is a bacterial secondary transporter with high-resolution crystal structures available for both the outward- and inward-facing conformations. Through molecular dynamics simulations of the ligand-free Mhp1 as well as analysis of its crystal structures, here we show that two inter-helical loops, respectively located at the extra- and intracellular ends of the “hash motif” in the protein, play important roles in the conformational transition. In the outward- and inward-facing states of the protein, the loops adopt different secondary structures, either wrapped to the end of an alpha-helix, or unwrapped to extended conformations. In equilibrium simulations of 100 ns with Mhp1 in explicit lipids and water, the loop conformations remain largely stable. In targeted molecular dynamics simulations with the protein structure driven from one state to the other, the loops exhibit resistance and only undergo abrupt changes when other parts of the protein already approach the target conformation. Free energy calculations on the isolated loops further confirm that the wrapping/unwrapping transitions are associated with substantial energetic barriers, and consist of multiple sequential steps involving the rotation of certain backbone torsion angles. Furthermore, in simulations with the loops driven from one state to the other, a large part of the protein follows the loops to the target conformation. Taken together, our simulations suggest that changes of the loop secondary structures would be among the slow degrees of freedom in the conformational transition of the entire protein. Incorporation of detailed loop structures into the reaction coordinate, therefore, should improve the convergence and relevance of the resulting conformational free energy.
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    Executable Specs: What Makes One, and How are They Used?
    (2006) Schubert, Peter J.; Vitkin, Lev; Winters, Frank
    Model-based systems development relies upon the concept of an executable specification. A survey of published literature shows a wide range of definitions for executable specifications [1-10]. In this paper, we attempt to codify the essential starting elements for a complete executable specification-based design flow. A complete executable specification that includes a functional model as well as test cases, in addition to a traditional prose document, is needed to transfer requirements from a customer to a supplier, or from a systems engineer to electrical hardware and software engineers. In the complete form demonstrated here, sub-components of a functionally-decomposed system manifest as modular reuse blocks suitable for publication in functional libraries. The overarching definition provided by product architecture and by software architecture must also be harmoniously integrated with design and implementation. Using seven specific automotive examples, we illustrate effective ways in which executable specifications have been used in production-ready applications. Benefits of model-based development are captured, including earlier and more thorough testing, automatic document generation, and autocode generation.