Molecular dynamics simulation of drug resistance in HIV-1 protease and reverse transcriptase

The emergence of drug resistant strains of HIV represents a major challenge in the treatment of patients who contract the virus. We investigate the use of classical molecular dynamics to give quantitative and qualitative molecular insight into the causes of resistance in the two main drug targets in HIV, protease and reverse transcriptase. We initially establish a simulation and free energy analysis protocol for the study of resistance in protease. Focusing on the binding of the inhibitor lopinavir to a series of six mutants with increasing resistance we demonstrate that ensemble simulations exhibit significantly enhanced thermodynamic sampling over single long simulations. We achieve accurate and converged relative binding free energies, reproducible to within 0.5 kcal mol^-1. The experimentally derived ranking of the systems is reproduced with a correlation coefficient of 0.89 and a mean relative deviation from experiment of 0.9 kcal mol^-1. Our protocol is then applied to investigate a patient derived viral sequence for which contradictory resistance assessments for lopinavir were obtained from existing clinical decision support systems (CDSS). Mutations at only three locations (L10I, A71I/V and L90M) in uenced the ranking. Free energies were computed for HXB2 wildtype sequences incorporating each mutation individually and all possible combinations, along with the full patient sequence. Only in the case of the patient sequence was any resistance observed. This observation suggests an explanation for the discordance found using the CDSS. The effects on drug binding of the mutations at positions 10, 71 and 90 appear to be highly dependent on the background mutations present in the remainder of the sequence. In preparation for the extension of our simulation and free energy protocol to reverse transcriptase the impact of binding both natural DNA substrates and two non nucleoside reverse transcriptase inhibitor (NNRTI) class drugs on the dynamics of reverse transcriptase are investigated. Free energies of both inhibitors (efavirenz and neviripine) are determined which are seen to be independent of the subdomain motions of the protein observed during simulation. Preliminary calculations of the free energies for a set of NNRTI resistant mutants bound to efavirenz are also presented

Putting the User at the Centre of the Grid: Simplifying Usability and Resource Selection for High Performance Computing

Computer simulation is finding a role in an increasing number of scientific disciplines, concomitant with the rise in available computing power. Realizing this inevitably re- quires access to computational power beyond the desktop, making use of clusters, supercomputers, data repositories, networks and distributed aggregations of these re- sources. Accessing one such resource entails a number of usability and security prob- lems; when multiple geographically distributed resources are involved, the difficulty is compounded. However, usability is an all too often neglected aspect of computing on e-infrastructures, although it is one of the principal factors militating against the widespread uptake of distributed computing. The usability problems are twofold: the user needs to know how to execute the applications they need to use on a particular resource, and also to gain access to suit- able resources to run their workloads as they need them. In this thesis we present our solutions to these two problems. Firstly we propose a new model of e-infrastructure resource interaction, which we call the user–application interaction model, designed to simplify executing application on high performance computing resources. We describe the implementation of this model in the Application Hosting Environment, which pro- vides a Software as a Service layer on top of distributed e-infrastructure resources. We compare the usability of our system with commonly deployed middleware tools using five usability metrics. Our middleware and security solutions are judged to be more usable than other commonly deployed middleware tools. We go on to describe the requirements for a resource trading platform that allows users to purchase access to resources within a distributed e-infrastructure. We present the implementation of this Resource Allocation Market Place as a distributed multi- agent system, and show how it provides a highly flexible, efficient tool to schedule workflows across high performance computing resources

A service-oriented Grid environment with on-demand QoS support

Grid Computing entstand aus der Vision für eine neuartige Recheninfrastruktur, welche darauf abzielt, Rechenkapazität so einfach wie Elektrizität im Stromnetz (power grid) verfügbar zu machen. Der entsprechende Zugriff auf global verteilte Rechenressourcen versetzt Forscher rund um den Globus in die Lage, neuartige Herausforderungen aus Wissenschaft und Technik in beispiellosem Ausmaß in Angriff zu nehmen. Die rasanten Entwicklungen im Grid Computing begünstigten auch Standardisierungsprozesse in Richtung Harmonisierung durch Service-orientierte Architekturen und die Anwendung kommerzieller Web Services Technologien. In diesem Kontext ist auch die Sicherung von Qualität bzw. entsprechende Vereinbarungen über die Qualität eines Services (QoS) wichtig, da diese vor allem für komplexe Anwendungen aus sensitiven Bereichen, wie der Medizin, unumgänglich sind. Diese Dissertation versucht zur Entwicklung im Grid Computing beizutragen, indem eine Grid Umgebung mit Unterstützung für QoS vorgestellt wird. Die vorgeschlagene Grid Umgebung beinhaltet eine sichere Service-orientierte Infrastruktur, welche auf Web Services Technologien basiert, sowie bedarfsorientiert und automatisiert HPC Anwendungen als Grid Services bereitstellen kann. Die Grid Umgebung zielt auf eine kommerzielle Nutzung ab und unterstützt ein durch den Benutzer initiiertes, fallweises und dynamisches Verhandeln von Serviceverträgen (SLAs). Das Design der QoS Unterstützung ist generisch, jedoch berücksichtigt die Implementierung besonders die Anforderungen von rechenintensiven und zeitkritischen parallelen Anwendungen, bzw. Garantien f¨ur deren Ausführungszeit und Preis. Daher ist die QoS Unterstützung auf Reservierung, anwendungsspezifische Abschätzung und Preisfestsetzung von Ressourcen angewiesen. Eine entsprechende Evaluation demonstriert die Möglichkeiten und das rationale Verhalten der QoS Infrastruktur. Die Grid Infrastruktur und insbesondere die QoS Unterstützung wurde in Forschungs- und Entwicklungsprojekten der EU eingesetzt, welche verschiedene Anwendungen aus dem medizinischen und bio-medizinischen Bereich als Services zur Verfügung stellen. Die EU Projekte GEMSS und Aneurist befassen sich mit fortschrittlichen HPC Anwendungen und global verteilten Daten aus dem Gesundheitsbereich, welche durch Virtualisierungstechniken als Services angeboten werden. Die Benutzung von Gridtechnologie als Basistechnologie im Gesundheitswesen ermöglicht Forschern und Ärzten die Nutzung von Grid Services in deren Arbeitsumfeld, welche letzten Endes zu einer Verbesserung der medizinischen Versorgung führt.Grid computing emerged as a vision for a new computing infrastructure that aims to make computing resources available as easily as electric power through the power grid. Enabling seamless access to globally distributed IT resources allows dispersed users to tackle large-scale problems in science and engineering in unprecedented ways. The rapid development of Grid computing also encouraged standardization, which led to the adoption of a service-oriented paradigm and an increasing use of commercial Web services technologies. Along these lines, service-level agreements and Quality of Service are essential characteristics of the Grid and specifically mandatory for Grid-enabling complex applications from certain domains such as the health sector. This PhD thesis aims to contribute to the development of Grid technologies by proposing a Grid environment with support for Quality of Service. The proposed environment comprises a secure service-oriented Grid infrastructure based on standard Web services technologies which enables the on-demand provision of native HPC applications as Grid services in an automated way and subject to user-defined QoS constraints. The Grid environment adopts a business-oriented approach and supports a client-driven dynamic negotiation of service-level agreements on a case-by-case basis. Although the design of the QoS support is generic, the implementation emphasizes the specific requirements of compute-intensive and time-critical parallel applications, which necessitate on-demand QoS guarantees such as execution time limits and price constraints. Therefore, the QoS infrastructure relies on advance resource reservation, application-specific resource capacity estimation, and resource pricing. An experimental evaluation demonstrates the capabilities and rational behavior of the QoS infrastructure. The presented Grid infrastructure and in particular the QoS support has been successfully applied and demonstrated in EU projects for various applications from the medical and bio-medical domains. The EU projects GEMSS and Aneurist are concerned with advanced e-health applications and globally distributed data sources, which are virtualized by Grid services. Using Grid technology as enabling technology in the health domain allows medical practitioners and researchers to utilize Grid services in their clinical environment which ultimately results in improved healthcare