Complex macrocycle exploration: parallel, heuristic, and constraint-based conformer generation using ForceGen.

ForceGen is a template-free, non-stochastic approach for 2D to 3D structure generation and conformational elaboration for small molecules, including both non-macrocycles and macrocycles. For conformational search of non-macrocycles, ForceGen is both faster and more accurate than the best of all tested methods on a very large, independently curated benchmark of 2859 PDB ligands. In this study, the primary results are on macrocycles, including results for 431 unique examples from four separate benchmarks. These include complex peptide and peptide-like cases that can form networks of internal hydrogen bonds. By making use of new physical movements ("flips" of near-linear sub-cycles and explicit formation of hydrogen bonds), ForceGen exhibited statistically significantly better performance for overall RMS deviation from experimental coordinates than all other approaches. The algorithmic approach offers natural parallelization across multiple computing-cores. On a modest multi-core workstation, for all but the most complex macrocycles, median wall-clock times were generally under a minute in fast search mode and under 2 min using thorough search. On the most complex cases (roughly cyclic decapeptides and larger) explicit exploration of likely hydrogen bonding networks yielded marked improvements, but with calculation times increasing to several minutes and in some cases to roughly an hour for fast search. In complex cases, utilization of NMR data to constrain conformational search produces accurate conformational ensembles representative of solution state macrocycle behavior. On macrocycles of typical complexity (up to 21 rotatable macrocyclic and exocyclic bonds), design-focused macrocycle optimization can be practically supported by computational chemistry at interactive time-scales, with conformational ensemble accuracy equaling what is seen with non-macrocyclic ligands. For more complex macrocycles, inclusion of sparse biophysical data is a helpful adjunct to computation

Identification of Class I HLA T Cell Control Epitopes for West Nile Virus

The recent West Nile virus (WNV) outbreak in the United States underscores the importance of understanding human immune responses to this pathogen. Via the presentation of viral peptide ligands at the cell surface, class I HLA mediate the T cell recognition and killing of WNV infected cells. At this time, there are two key unknowns in regards to understanding protective T cell immunity: 1) the number of viral ligands presented by the HLA of infected cells, and 2) the distribution of T cell responses to these available HLA/viral complexes. Here, comparative mass spectroscopy was applied to determine the number of WNV peptides presented by the HLA-A*11:01 of infected cells after which T cell responses to these HLA/WNV complexes were assessed. Six viral peptides derived from capsid, NS3, NS4b, and NS5 were presented. When T cells from infected individuals were tested for reactivity to these six viral ligands, polyfunctional T cells were focused on the GTL9 WNV capsid peptide, ligands from NS3, NS4b, and NS5 were less immunogenic, and two ligands were largely inert, demonstrating that class I HLA reduce the WNV polyprotein to a handful of immune targets and that polyfunctional T cells recognize infections by zeroing in on particular HLA/WNV epitopes. Such dominant HLA/peptide epitopes are poised to drive the development of WNV vaccines that elicit protective T cells as well as providing key antigens for immunoassays that establish correlates of viral immunity. © 2013 Kaabinejadian et al

A performance simulation tool for the analysis of data gathering in both terrestrial and underwater sensor networks

Wireless sensor networks (WSNs) have greatly contributed to human-associated technologies. The deployment of WSNs has transcended several paradigms. Two of the most significant features of WSNs are the intensity of deployment and the criticalness of the applications that they govern. The tradeoff between volume and cost requires justified investments for evaluating the multitudes of hardware and complementary software options. In underwater sensor networks (USNs), testing any technique is not only costly but also difficult in terms of full deployment. Therefore, evaluation prior to the actual procurement and setup of a WSN and USN is an extremely important step. The spectrum of performance analysis tools encompassing the test-bed, analysis, and simulation has been able to provide the prerequisites that these evaluations require. Simulations have proven to be an extensively used tool for analysis in the computer network field. A number of simulation tools have been developed for wired/wireless radio networks. However, each simulation tool has several restrictions when extended to the analysis of WSNs. These restrictions are largely attributed to the unique nature of each WSN within a designated area of research. In addition, these tools cannot be used for underwater environments with an acoustic communication medium, because there is a wide range of differences between radio and acoustic communications. The primary purpose of this paper is to present, propose, and develop a discrete event simulation designed specifically for mobile data gathering in WSNs. In addition, this simulator has the ability to simulate 2-D USNs. This simulator has been tailored to cater to both mobile and static data gathering techniques for both topologies, which are either dense or light. The results obtained using this simulator have shown an evolving efficient simulator for both WSNs and USNs. The developed simulator has been extensively tested in terms of its validity and scope of governance

A methodology for the design of application-specific cyber-physical social sensing co-simulators

Cyber-Physical Social Sensing (CPSS) is a new trend in the context of pervasive sensing. In these new systems, various domains coexist in time, evolve together and influence each other. Thus, application-specific tools are necessary for specifying and validating designs and simulating systems. However, nowadays, different tools are employed to simulate each domain independently. Mainly, the cause of the lack of co-simulation instruments to simulate all domains together is the extreme difficulty of combining and synchronizing various tools. In order to reduce that difficulty, an adequate architecture for the final co-simulator must be selected. Therefore, in this paper the authors investigate and propose a methodology for the design of CPSS co-simulation tools. The paper describes the four steps that software architects should follow in order to design the most adequate co-simulator for a certain application, considering the final users’ needs and requirements and various additional factors such as the development team’s experience. Moreover, the first practical use case of the proposed methodology is provided. An experimental validation is also included in order to evaluate the performing of the proposed co-simulator and to determine the correctness of the proposal

FORLORN: A Framework for Comparing Offline Methods and Reinforcement Learning for Optimization of RAN Parameters

The growing complexity and capacity demands for mobile networks necessitate innovative techniques for optimizing resource usage. Meanwhile, recent breakthroughs have brought Reinforcement Learning (RL) into the domain of continuous control of real-world systems. As a step towards RL-based network control, this paper introduces a new framework for benchmarking the performance of an RL agent in network environments simulated with ns-3. Within this framework, we demonstrate that an RL agent without domain-specific knowledge can learn how to efficiently adjust Radio Access Network (RAN) parameters to match offline optimization in static scenarios, while also adapting on the fly in dynamic scenarios, in order to improve the overall user experience. Our proposed framework may serve as a foundation for further work in developing workflows for designing RL-based RAN control algorithms

Mapping specificity, cleavage entropy, allosteric changes and substrates of blood proteases in a high-throughput screen

Proteases are among the largest protein families and critical regulators of biochemical processes like apoptosis and blood coagulation. Knowledge of proteases has been expanded by the development of proteomic approaches, however, technology for multiplexed screening of proteases within native environments is currently lacking behind. Here we introduce a simple method to profile protease activity based on isolation of protease products from native lysates using a 96FASP filter, their analysis in a mass spectrometer and a custom data analysis pipeline. The method is significantly faster, cheaper, technically less demanding, easy to multiplex and produces accurate protease fingerprints. Using the blood cascade proteases as a case study, we obtain protease substrate profiles that can be used to map specificity, cleavage entropy and allosteric effects and to design protease probes. The data further show that protease substrate predictions enable the selection of potential physiological substrates for targeted validation in biochemical assays

Study on the Impact of the NS in the Performance of Meta-Heuristics in the TSP

Meta-heuristics have been applied for a long time to the Travelling Salesman Problem (TSP) but information is still lacking in the determination of the parameters with the best performance. This paper examines the impact of the Simulated Annealing (SA) and Discrete Artificial Bee Colony (DABC) parameters in the TSP. One special consideration of this paper is how the Neighborhood Structure (NS) interact with the other parameters and impacts the performance of the meta-heuristics. NS performance has been the topic of much research, with NS proposed for the best-known problems, which seem to imply that the NS influences the performance of meta-heuristics, more that other parameters. Moreover, a comparative analysis of distinct meta-heuristics is carried out to demonstrate a non-proportional increase in the performance of the NS.This work is supported by FEDER Funds through the "Programa Operacional Factores de Competitividade - COMPETE" program and by National Funds through FCT "FundaqAo para a Ciencia e a Tecnologia" under the project: FCOMP-01-0124-FEDER-PEst-OE/EEl/U10760/2011, PEst-OE/EEI/UI0760/2014, and PEst2015-2020.info:eu-repo/semantics/publishedVersio