Berhanu, Workalemahu Mikre
01 January 2011
Amyloids are highly ordered cross-β sheet aggregates that are associated with many diseases such as Alzheimer‟s, type II diabetes and prion diseases. Recently a progress has been made in structure elucidation, environmental effects and thermodynamic properties of amyloid aggregates. However, detailed understanding of how mutation, packing polymorphism and small organic molecules influence amyloid structure and dynamics is still lacking. Atomistic modeling of these phenomena with molecular dynamics (MD) simulations holds a great promise to bridge this gap. This Thesis describes the results of MD simulations, which provide insight into the effects of mutation, packing polymorphism and molecular inhibitors on amyloid peptides aggregation. Chapter 1 discusses the structure of amyloid peptides, diseases associated with amyloid aggregation, mechanism of aggregation and strategies to treat amyloid diseases. Chapter 2 describes the basic principles of molecular dynamic simulation and methods of trajectory analysis used in the Thesis. Chapter 3 presents the results of the study of several all-atom molecular dynamics simulations with explicit solvent, starting from the crystalline fragments of two to ten monomers each. Three different hexapeptides and their analogs produced with single glycine replacement were investigated to study the structural stability, aggregation behavior and thermodynamics of the amyloid oligomers. Chapter 4 presents multiple molecular dynamics (MD) simulation of a pair polymorphic form of five short segments of amyloid peptide. Chapter 5 describes MD study of single-layer oligomers of the full-length insulin with a goal to identify the structural elements that are important for insulin amyloid stability, and to suggest single glycine mutants that may improve formulation. Chapter 6 presents the investigation of the mechanism of the interaction of polyphenols molecules with the protofibrils formed by an amyloidogenic hexapeptide fragment (VQIVYK) of Tau peptide by molecular dynamics iii simulations in explicit solvent. We analyzed the trajectories of the large (7×4) aggregate with and without the polyphenols. Our MD simulations for both the short and full length amyloids revealed adding strands enhances the internal stability of wildtype aggregates. The degree of structural similarity between the oligomers in simulation and the fibril models constructed based on experimental data may explain why adding oligomers shortens the experimentally observed nucleation lag phase of amyloid aggregation. The MM-PBSA free energy calculation revealed nonpolar components of the free energy is more favorable while electrostatic solvation is unfavorable for the sheet to sheet interaction. This explains the acceleration of aggregation by adding nonpolar co-solvents (methanol, trifluoroethanol, and hexafluoroisopropanol). Free energy decomposition shows residues situated at the interface were found to make favorable contribution to the peptide -peptide association. The results from the simulations might provide both the valuable insight for amyloid aggregation as well as assist in inhibitor design efforts. First, the simulation of the single glycine mutants at the steric zipper of the short segments of various pathological peptides indicates the intersheet steric zipper is important for amyloid stability. Mutation of the side chains at the dry steric zipper disrupts the sheet to sheet packing, making the aggregation unstable. Thus, designing new peptidomimetic inhibitors able to prevent the fibril formation based on the steric zipper motif of the oligomers, similar to the ones examined in this study may become a viable therapeutic strategy. The various steric zipper microcrystal structures of short amyloid segments could be used as a template to design aggregation inhibitor that can block growth of the aggregates. Modification of the steric zipper structure (structure based design) with a single amino acid changes, shuffling the sequences, N- methylation of peptide amide bonds to suppress hydrogen iv bonding ability of NH groups or replacement with D amino acid sequence that interact with the parent steric zipper could be used in computational search for the new inhibitors. Second, the polyphenols were found to interact with performed oligomer through hydrogen bonding and induce conformational change creating an altered aggregate. The conformational change disrupts the intermolecular amyloid contact remodeling the amyloid aggregate. The recently reported microcrystal structure of short segments of amyloid peptides with small organic molecules could serve as a pharamcophore for virtual screening of aggregation inhibitor using combined docking and MD simulation with possible enhancement of lead enrichment. Finally, our MD simulation of short segments of amyloids with steric zipper polymorphism showed the stability depends on both sequence and packing arrangements. The hydrophilic polar GNNQQNY and NNQNTF with interface containing large polar and/or aromatic side chains (Q/N) are more stable than steric zipper interfaces made of small or hydrophobic residues (SSTNVG, VQIVYK, and MVGGVV). The larger sheet to sheet interface of the dry steric zipper through polar Q/N rich side chains was found to holds the sheets together better than non Q/N rich short amyloid segments. The packing polymorphism could influence the structure based design of aggregation inhibitor and a combination of different aggregation inhibitors might be required to bind to various morphologic forms of the amyloid peptides.
Anderson, Karen M.
01 October 1982
(has links) (PDF)
The flow of traffic at an intersection is often controlled by a traffic signal. This research report models a T-intersection with a disjoint network for each direction of traffic flow, eastbound, westbound and southbound. The traffic signal is modeled with a fourth network. Three types of signal control (pretimed, semi-actuated and full-actuated) are modeled to examine the effect of each type on the average delay time and average length of queues for each lane of traffic queue at the intersection. The computer models presented in the report use SLAM computer language to simulate the traffic signal and vehicle flow.
Jang, Duh, 1957-
The thesis describes a realization of distributed experimental frame concepts in DEVS-SCHEME, an object-oriented simulation environment. Also discussed, are the design and implementation issues concerning the attachments of frame components to a model in a given model structure. The algorithm for the attachments is derived to set up the model composition and model couplings when needed. An example of a simplified computer system which consists of a CPU, and a memory management (MGMT), is presented to demonstrate how such a system is observed and experimented with under centralized and decentralized experimental frames. A graphical interactive interface is provided to facilitate the attachments of frame components to models. The simulation shows that the theory regarding decentralized experimental frames is correct and feasible. Some prospective research topics and future study activities are also brought up.
Development of an empirical force field and molecular dynamics simulation of N,N'-dialkylimidazolium ionic liquidsMusanur Abrar, Siraj 03 1900 (has links)
Thesis (MSc)--Stellenbosch University, 2004 / ENGLISH ABSTRACT: In an ongoing study an empirical force field that can correctly model N,N'- dialkylimidazolium halide ionic liquids, the Imidazolium Ionic Liquid Force Field - IILFF, was developed based on experimental data obtained from the Cambridge Structural Database (CSD) and data calculated using Gaussian98. Different conformations of the isolated cations were optimised at the Hartree-Fock level using the 6-31G(d) basis set. Structural, vibrational and partial atomic charge data of the lowest energy conformation of each cation were taken as observables during optimisation of the force field parameters. Initial parameters of the IILFF were taken from existing force fields and were optimised using the above mentioned data. The IILFF was used to minimise isolated cations as well as crystals. These results were successfully tested against isolated cations minimised using Gaussian98 and the experimental crystals. Finally, the melting process of the 1,3-dimethylimidazolium chloride crystal was studied using an NPT ensemble starting from an ordered crystal cell and increasing the simulation temperature beyond the experimental melting temperature. The IILFF was then used to calculate the potential energy of the system. / AFRIKAANSE OPSOMMING: In 'n voortgaande studie om 'n empiriese kragveld te bou wat N,N' -dialkielimidasoliumhalied ioniese vloeistowwe korrek kan modelleer is die Imidasolium Ioniese Vloeistof Kragveld (nVK) ontwikkel. Die kragveld is ontwikkel gebasseer op eksperimentele data verkry uit die Cambridge Strukturele Databasis (CSD) asook uit data vanaf Gaussian98 berekeninge. Verskillende konformasies van die geïsoleerde katione is geoptimiseer deur middel van Hartree Fock 6-31G(d) berekeninge. Strukturele data, asook vibrasies en gedeeltelike atoom ladings van die laagste energie konformasie van elke katioon is gebruik as waarneembare veranderlikes vir die bepaling van die optimale kragveld parameters. Beginwaardes vir die nVK is geneem uit bestaande kragvelde en geoptimiseer met behulp van bogenoemde data. Die IIVK is gebruik om geïsoleerde katione asook kristalle te minimiseer. Die resultate is suksesvol getoets teen geïsoleerde katione wat met behulp van Gaussian98 geminimiseer is en eksperimenteel bepaalde kristalle. Laastens is die smeltproses van die 1,3-dimetielimidasolium chloried kristal bestudeer met behulp van 'n NPT ensemble. Daar is begin by 'n geordende kristal en die simulasie temperatuur is verhoog tot meer as die eksperimentele smeltpunt. Die IIVK is dan gebruik om die potensiële energie van die sisteem te bepaal.
James, Steven Doron
A dissertation submitted to the Faculty of Science, University of the Witwatersrand, in fulfilment of the requirements for the degree of Master of Science. August 2016. / Monte Carlo Tree Search (MCTS) is a family of directed search algorithms that has gained widespread attention in recent years. It combines a traditional tree-search approach with Monte Carlo simulations, using the outcome of these simulations (also known as playouts or rollouts) to evaluate states in a look-ahead tree. That MCTS does not require an evaluation function makes it particularly well-suited to the game of Go — seen by many to be chess’s successor as a grand challenge of artificial intelligence — with MCTS-based agents recently able to achieve expert-level play on 19×19 boards. Furthermore, its domain-independent nature also makes it a focus in a variety of other fields, such as Bayesian reinforcement learning and general game-playing. Despite the vast amount of research into MCTS, the dynamics of the algorithm are still not yet fully understood. In particular, the effect of using knowledge-heavy or biased simulations in MCTS still remains unknown, with interesting results indicating that better-informed rollouts do not necessarily result in stronger agents. This research provides support for the notion that MCTS is well-suited to a class of domain possessing a smoothness property. In these domains, biased rollouts are more likely to produce strong agents. Conversely, any error due to incorrect bias is compounded in non-smooth domains, and in particular for low-variance simulations. This is demonstrated empirically in a number of single-agent domains. / LG2017
A theoretical study of metabolic regulation in bacteria based on in silico models and high-throughput dataYang, Zhu 01 January 2009 (has links)
No description available.
Grenney, William J.
16 October 1970
A digital computer model was developed to simulate the time and space distribution of a dissolved pollutant in an estuary. The program is basically a one-dimensional finite-difference model, but two dimensions can be represented by attaching together several one-dimensional channels. The influence of convection, dispersion and decay are included in the model. The time scale is based on increments of less than one tidal cycle so that intertidal velocities are represented. A sensitivity analysis was conducted on the convection portion of the model and several tables and graphs are included to indicate the nature and magnitude of numerical errors associated with the model. A method for correcting these errors is also presented. A tracer study was conducted on the Yaquina Estuary, Newport, Oregon and results are compared with two computer model simulations. / Graduation date: 1971
Steady-state analysis in simulation : an application of Schriber's truncation rule to complex queueing systemsSaleh, Budiman 12 December 1991 (has links)
The objective of many steady-state simulations is to study the behavior of a nonterminating system with a peak load of infinite duration. Due to the complexity of the system, the initial conditions of the system are often atypical that often requires the simulators to start the system with the empty and idle conditions. Consequently, deletion of some initial observations is required to reduce the initialization bias induced by atypical initial conditions. This paper studies the application of Schriber's truncation rule to the complex queueing systems (specifically, the two-machine and three-machine tandem queueing system) and the effects of parameter selection (i.e. parameters batch size and time between observations) on performance measures. Based on the previous studies of Schriber's rule on the one-machine system, parameters batch count and tolerance are held constant. Mean-squared error and half length are used as measures of accuracy and interval precision in comparing the results. The results of both systems show that time between observations and batch size are significant parameters, and the recommendations for the two-machine system can be generalized for the three-machine system. Increasing the number of machines in the system from two to three requires a careful reduction in the value of time between observations. Besides, multiple replications should be used to minimize the extreme results in determining the steady-state mean number of entities and the truncation point. / Graduation date: 1992
Balestrini Robinson, Santiago.
Thesis (Ph.D)--Aerospace Engineering, Georgia Institute of Technology, 2010. / Committee Chair: Mavris, Dimitri; Committee Member: Bishop, Carlee; Committee Member: German, Brian; Committee Member: Nixon, Janel; Committee Member: Schrage, Daniel. Part of the SMARTech Electronic Thesis and Dissertation Collection.
Understanding the importance of taxonomic sampling for large-scale phylogenetic analyses by simulating evolutionary processes under complex modelsHeath, Tracy Ann 12 October 2012 (has links)
Appropriate and extensive taxon sampling is one of the most important determinants of accurate phylogenetic estimation. In addition, accuracy of inferences about evolutionary processes obtained from phylogenetic analyses is improved significantly by thorough taxon sampling efforts. Much of the previous work examining the impact of taxon sampling on phylogenetic accuracy has focused on the effects of random taxon sampling or directed taxon addition/removal. Therefore, the effect of realistic, nonrandom taxon sampling strategies on the accuracy of large-scale phylogenetic reconstruction is not well understood. Typically, broad systematic studies of diverse clades select species according to current classification to span the diversity within the group of interest. I simulated phylogenies under a realistic model of cladogenesis and used these trees to generate sequence data. Using these simulations, I explored the effect of taxonomy-based taxon sampling on the accuracy of maximum likelihood reconstruction. The results demonstrate that taxonomy-based sampling has a stronger, negative, effect on phylogenetic accuracy than random taxon sampling. Therefore, it is recommended that systematists conducting phylogenetic analyses of diverse clades concentrate on improving sampling density within their group of interest by selecting multiple representatives from each taxonomic level. Phylogenetic tree imbalance is often used to make inferences about macroevolutionary processes that generate patterns of tree shape. However these patterns may be obscured by non-biological factors that can bias tree shape. Using published trees inferred from biological data and trees simulated under a realistic branching model; I investigated the affect of random taxon omission on phylogenetic tree imbalance. My results indicate that incomplete taxon sampling in the presence of variable rates of speciation and extinction may be sufficient to explain much of the imbalance observed in empirical phylogenies. Previous research has indicated that some methods of phylogenetic inference can produce biased tree topologies and shapes. Using simulated model tree topologies and sequence data, I investigated the non-biological factors that lead to biases in phylogenetic tree imbalance. Based on my results, I concluded that phylogenetic noise is the primary cause of tree shape bias. Methods that account for unobserved substitutions, such as maximum likelihood, can overcome the systematic bias toward imbalanced topologies. / text
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