Parallel and Distributed Computing

The 14 chapters presented in this book cover a wide variety of representative works ranging from hardware design to application development. Particularly, the topics that are addressed are programmable and reconfigurable devices and systems, dependability of GPUs (General Purpose Units), network topologies, cache coherence protocols, resource allocation, scheduling algorithms, peertopeer networks, largescale network simulation, and parallel routines and algorithms. In this way, the articles included in this book constitute an excellent reference for engineers and researchers who have particular interests in each of these topics in parallel and distributed computing

Combined optimization algorithms applied to pattern classification

Accurate classification by minimizing the error on test samples is the main goal in pattern classification. Combinatorial optimization is a well-known method for solving minimization problems, however, only a few examples of classifiers axe described in the literature where combinatorial optimization is used in pattern classification. Recently, there has been a growing interest in combining classifiers and improving the consensus of results for a greater accuracy. In the light of the "No Ree Lunch Theorems", we analyse the combination of simulated annealing, a powerful combinatorial optimization method that produces high quality results, with the classical perceptron algorithm. This combination is called LSA machine. Our analysis aims at finding paradigms for problem-dependent parameter settings that ensure high classifica, tion results. Our computational experiments on a large number of benchmark problems lead to results that either outperform or axe at least competitive to results published in the literature. Apart from paxameter settings, our analysis focuses on a difficult problem in computation theory, namely the network complexity problem. The depth vs size problem of neural networks is one of the hardest problems in theoretical computing, with very little progress over the past decades. In order to investigate this problem, we introduce a new recursive learning method for training hidden layers in constant depth circuits. Our findings make contributions to a) the field of Machine Learning, as the proposed method is applicable in training feedforward neural networks, and to b) the field of circuit complexity by proposing an upper bound for the number of hidden units sufficient to achieve a high classification rate. One of the major findings of our research is that the size of the network can be bounded by the input size of the problem and an approximate upper bound of 8 + √2n/n threshold gates as being sufficient for a small error rate, where n := log/SL and SL is the training set

Biophysical and computational characterisation of the disorder-to-order structural transition of the small hydrophilic endoplasmic-reticulum associated protein, SHERP

This thesis explores the disorder-to-order structural transition of the small hydrophilic endoplasmic reticulum associated protein (SHERP). SHERP has been shown to be essential to the life cycle of Leishmania major, a parasite responsible for leishmaniasis which kills tens of thousands every year. The protein is almost entirely disordered in solution, but undergoes a dramatic increase in helicity upon binding to anionic lipids or detergents. Although the ordered structure of SHERP had previously been solved by solution nuclear magnetic resonance spectroscopy in the presence of sodium dodecyl sulphate (SDS), both the nature of the disordered ensemble of the protein and the organisation of the SHERP/detergent complex were unknown. Using a combination of synchrotron radiation circular dichroism spectroscopy (SRCD), small angle X-ray scattering (SAXS) and molecular dynamics (MD), several projects were carried out exploring the disorder-to-order structural transition of SHERP in the presence of SDS. The effectiveness of sequence-based predictors to estimate the effect of single mutants was explored, with a number of mutants expressed and characterised by SRCD and MD. A mutant, the “permutant”, was designed with the aim of decreasing the disorder of the protein in solution while maintaining amino acid composition, by introduction of multiple potential i → i4 salt bridges created by permutations of the wild-type sequence. Molecular dynamics simulations of the wild-type and “permutant” construct found a dramatic increase in salt bridge formation, and in vitro characterisation of the “permutant” construct showed it had significantly greater helical character than the wild-type in the absence of SDS. The disordered ensemble of SHERP was characterised by replica exchange MD, SRCD and SAXS. Good agreement was found between simulation and experiment, with a predominantly unfolded ensemble deficient in secondary structure described by our results. The changes that occur upon SHERP binding to SDS were also characterised. MD simulation of the SHERP-SDS complex showed that the protein bound among the head-groups of the SDS micelle, and the helical content and helix-turn-helix structure was retained. It also allowed identification of several cationic side-chains which formed stabilising salt bridges with the sulphates of SDS. The complex was then characterised in vitro, by SAXS and CD spectroscopy. The addition of the protein led to a doubling in micelle length, with multiple SHERP molecules found to bind to the anionic head-groups in the shell of the micelle. The residues identified during the MD simulation were substituted with alanine to make a series of mutants with increasing negative charge. Significant decreases in helicity, micelle length and the numbers of protein bound occurred as negative charge increased, possibly caused by decreased affinity of the protein for the micelle causing less protein molecules to bind per micelle, leading to a decreased chance of stabilising protein-protein interactions resulting in partial folding of the protein. These results demonstrate the importance of charge-charge interactions in the disorder-to-order structural transition of SHERP, and provide structural context for future functional work on this protein

Enumeration, conformation sampling and population of libraries of peptide macrocycles for the search of chemotherapeutic cardioprotection agents

Peptides are uniquely endowed with features that allow them to perturb previously difficult to drug biomolecular targets. Peptide macrocycles in particular have seen a flurry of recent interest due to their enhanced bioavailability, tunability and specificity. Although these properties make them attractive hit-candidates in early stage drug discovery, knowing which peptides to pursue is non‐trivial due to the magnitude of the peptide sequence space. Computational screening approaches show promise in their ability to address the size of this search space but suffer from their inability to accurately interrogate the conformational landscape of peptide macrocycles. We developed an in‐silico compound enumerator that was tasked with populating a conformationally laden peptide virtual library. This library was then used in the search for cardio‐protective agents (that may be administered, reducing tissue damage during reperfusion after ischemia (heart attacks)). Our enumerator successfully generated a library of 15.2 billion compounds, requiring the use of compression algorithms, conformational sampling protocols and management of aggregated compute resources in the context of a local cluster. In the absence of experimental biophysical data, we performed biased sampling during alchemical molecular dynamics simulations in order to observe cyclophilin‐D perturbation by cyclosporine A and its mitochondrial targeted analogue. Reliable intermediate state averaging through a WHAM analysis of the biased dynamic pulling simulations confirmed that the cardio‐protective activity of cyclosporine A was due to its mitochondrial targeting. Paralleltempered solution molecular dynamics in combination with efficient clustering isolated the essential dynamics of a cyclic peptide scaffold. The rapid enumeration of skeletons from these essential dynamics gave rise to a conformation laden virtual library of all the 15.2 Billion unique cyclic peptides (given the limits on peptide sequence imposed). Analysis of this library showed the exact extent of physicochemical properties covered, relative to the bare scaffold precursor. Molecular docking of a subset of the virtual library against cyclophilin‐D showed significant improvements in affinity to the target (relative to cyclosporine A). The conformation laden virtual library, accessed by our methodology, provided derivatives that were able to make many interactions per peptide with the cyclophilin‐D target. Machine learning methods showed promise in the training of Support Vector Machines for synthetic feasibility prediction for this library. The synergy between enumeration and conformational sampling greatly improves the performance of this library during virtual screening, even when only a subset is used

The architectural complexity of the human PDC core assembly

The mammalian pyruvate dehydrogenase complex (PDC) is a key multi-enzyme assembly linking the glycolytic pathway to the TCA cycle via the specific conversion of pyruvate to acetyl CoA and, as such, is responsible for the maintenance of glucose homeostasis in humans. PDC comprises a central pentagonal dodecahedral core of 60 dihydrolipoamide acetyltransferase (E2) and 12 E3 binding protein (E3BP) subunits. Presently, two conflicting models of PDC (E2+E3BP) core organisation exist: the ‘addition’ (60+12) and ‘substitution’ (48+12) models. In addition to its catalytic role, the multi-domain E2/E3BP core provides the structural framework to which 30 pyruvate decarboxylase (E1) heterotetramers and 6-12 dihydrolipoamide dehydrogenase (E3) homodimers are proposed to bind at maximal occupancy. The formation of specific E2:E1 and E3BP:E3 subcomplexes are characteristic of eukaryotic PDCs and are critical for normal complex function. Despite the availability of limited structural data, the exact subunit organisation and mechanism of operation of the mammalian E2/E3BP core remains unknown. This thesis describes the large-scale purification of tagged, recombinant human PDC cores, full-length rE2 and rE2/E3BP, truncated E2/E3BP, peripheral rE3 enzyme as well as native E2/E3BP core (bE2/E3BP) purified from bovine heart. The ability to purify large amounts of pure protein has enabled the characterisation of the individual cores as well as the E2/E3BP:E3 complex using a variety of biochemical and biophysical techniques. Full-length rE2/E3BP, rE2, bE2/E3BP, truncated E2/E3BP (tLi19/tLi30) and rE2/E3BP:E3 were analysed in solution by analytical ultracentrifugation (AUC). While AUC of the cores supported the substitution model of core organisation, the stoichiometry of interaction was determined to be 2:1 (rE2/E3BP:E3). This was further complemented by gel filtration chromatography (GFC) and small angle neutron scattering (SANS), implying the possible existence of a network of E3 ‘cross-bridges’ linking pairs of E3BP molecules across the surface of the E2 core assembly. Low resolution solution structures obtained for rE2/E3BP, bE2/E3BP and tLi19/tLi30 by small angle x-ray scattering (SAXS) and SANS revealed the presence of icosahedral cores with open pentagonal faces favouring the substitution model of core organisation. These solution structures also indicated high structural similarity between the recombinant and native cores, as well as with the crystal structure obtained previously for the truncated bacterial E2 core. In addition, homology modelling and superimpositions of high- and low-resolution structures of the core revealed conservation of the overall pentagonal dodecahedral morphology despite evolutionary diversity. Evidence for the substitution model of core organisation was further substantiated by negative stain EM of the recombinant and bovine E2/E3BP cores. SANS stoichiometry data indicated the binding of 10 E3 dimers per E2/E3BP core. Although this could correspond to approximately 1:1 stoichiometry between E2/E3BP:E3, subsequent radiolabelling studies suggested possible variation in core subunit composition between the native and recombinant E2/E3BP cores. Therefore, as opposed to the 48E2+12E3BP substitution model based on AUC and SAXS studies with the recombinant E2/E3BP core, rE2/E3BP cores produced in this study indicated a higher level of incorporation of E3BPs with a maximum core composition of 40E2+20E3BP. On the basis of this new finding we have proposed the ‘variable E3BP substitution model’, wherein the number of E3BPs within the core can range from 0 to a maximum of 20, thus resulting in variable populations of E2/E3BP cores. Despite this core variability, the highly controlled regulatory mechanisms in vivo may bias the core composition towards an average of 48E2+12E3BP. However, as the over-expression of the recombinant E2/E3BP core in our study is not as tightly regulated as in vivo, higher number of E3BPs (>12) is observed to be integrated into the core. This new level of architectural complexity and variable subunit composition in mammalian PDC core organisation is likely to have important implications for the catalytic mechanism, overall complex efficiency and tissue-specific regulation by the intrinsic PDC kinases (PDKs) in normal and disease states. The E2 cores of the PDC family are known to be highly flexible, exhibiting inherent size variability reflective of the ‘breathing’ of the core. Integration of E3BP into the E2 core assembly would then be expected to have significant consequences for the structural assembly, affecting the ‘breathing’ and in turn the function and regulation of the complex. Unfolding studies to assess core stability via circular dichroism (CD) and tryptophan fluorescence revealed lower stability of the rE2/E3BP core as compared to cores composed exclusively of rE2 subunits, thus implying the contribution of E3BP towards core destabilisation. In addition, crosslinking studies indicated weak dimerisation of rE3BP, which may be a key factor promoting core destabilisation. The lower stability of the E2/E3BP core may be of benefit in mammals where sophisticated fine tuning is required to obtain cores with optimal catalytic and regulatory efficiencies. SAXS solution structures of E2/E3BP cores obtained were unable to locate the exact positions of E3BP within the core. However, SANS in combination with contrast matching of selectively deuterated components as well as cryo-EM, EM tomography and single molecule studies could be used in future for determination of the exact locations of E3BP, and validating the importance of E2/E3BP core organisation and subunit composition for overall PDC function and regulation

Using MapReduce Streaming for Distributed Life Simulation on the Cloud

Distributed software simulations are indispensable in the study of large-scale life models but often require the use of technically complex lower-level distributed computing frameworks, such as MPI. We propose to overcome the complexity challenge by applying the emerging MapReduce (MR) model to distributed life simulations and by running such simulations on the cloud. Technically, we design optimized MR streaming algorithms for discrete and continuous versions of Conway’s life according to a general MR streaming pattern. We chose life because it is simple enough as a testbed for MR’s applicability to a-life simulations and general enough to make our results applicable to various lattice-based a-life models. We implement and empirically evaluate our algorithms’ performance on Amazon’s Elastic MR cloud. Our experiments demonstrate that a single MR optimization technique called strip partitioning can reduce the execution time of continuous life simulations by 64%. To the best of our knowledge, we are the first to propose and evaluate MR streaming algorithms for lattice-based simulations. Our algorithms can serve as prototypes in the development of novel MR simulation algorithms for large-scale lattice-based a-life models.https://digitalcommons.chapman.edu/scs_books/1014/thumbnail.jp