High-throughput Binding Affinity Calculations at Extreme Scales

Resistance to chemotherapy and molecularly targeted therapies is a major factor in limiting the effectiveness of cancer treatment. In many cases, resistance can be linked to genetic changes in target proteins, either pre-existing or evolutionarily selected during treatment. Key to overcoming this challenge is an understanding of the molecular determinants of drug binding. Using multi-stage pipelines of molecular simulations we can gain insights into the binding free energy and the residence time of a ligand, which can inform both stratified and personal treatment regimes and drug development. To support the scalable, adaptive and automated calculation of the binding free energy on high-performance computing resources, we introduce the High- throughput Binding Affinity Calculator (HTBAC). HTBAC uses a building block approach in order to attain both workflow flexibility and performance. We demonstrate close to perfect weak scaling to hundreds of concurrent multi-stage binding affinity calculation pipelines. This permits a rapid time-to-solution that is essentially invariant of the calculation protocol, size of candidate ligands and number of ensemble simulations. As such, HTBAC advances the state of the art of binding affinity calculations and protocols

A planning approach to the automated synthesis of template-based process models

The design-time specification of flexible processes can be time-consuming and error-prone, due to the high number of tasks involved and their context-dependent nature. Such processes frequently suffer from potential interference among their constituents, since resources are usually shared by the process participants and it is difficult to foresee all the potential tasks interactions in advance. Concurrent tasks may not be independent from each other (e.g., they could operate on the same data at the same time), resulting in incorrect outcomes. To tackle these issues, we propose an approach for the automated synthesis of a library of template-based process models that achieve goals in dynamic and partially specified environments. The approach is based on a declarative problem definition and partial-order planning algorithms for template generation. The resulting templates guarantee sound concurrency in the execution of their activities and are reusable in a variety of partially specified contextual environments. As running example, a disaster response scenario is given. The approach is backed by a formal model and has been tested in experiment

Using formal methods to support testing

Formal methods and testing are two important approaches that assist in the development of high quality software. While traditionally these approaches have been seen as rivals, in recent years a new consensus has developed in which they are seen as complementary. This article reviews the state of the art regarding ways in which the presence of a formal specification can be used to assist testing

Predicate Abstraction with Under-approximation Refinement

We propose an abstraction-based model checking method which relies on refinement of an under-approximation of the feasible behaviors of the system under analysis. The method preserves errors to safety properties, since all analyzed behaviors are feasible by definition. The method does not require an abstract transition relation to be generated, but instead executes the concrete transitions while storing abstract versions of the concrete states, as specified by a set of abstraction predicates. For each explored transition the method checks, with the help of a theorem prover, whether there is any loss of precision introduced by abstraction. The results of these checks are used to decide termination or to refine the abstraction by generating new abstraction predicates. If the (possibly infinite) concrete system under analysis has a finite bisimulation quotient, then the method is guaranteed to eventually explore an equivalent finite bisimilar structure. We illustrate the application of the approach for checking concurrent programs.Comment: 22 pages, 3 figures, accepted for publication in Logical Methods in Computer Science journal (special issue CAV 2005

Engineering simulations for cancer systems biology

Computer simulation can be used to inform in vivo and in vitro experimentation, enabling rapid, low-cost hypothesis generation and directing experimental design in order to test those hypotheses. In this way, in silico models become a scientific instrument for investigation, and so should be developed to high standards, be carefully calibrated and their findings presented in such that they may be reproduced. Here, we outline a framework that supports developing simulations as scientific instruments, and we select cancer systems biology as an exemplar domain, with a particular focus on cellular signalling models. We consider the challenges of lack of data, incomplete knowledge and modelling in the context of a rapidly changing knowledge base. Our framework comprises a process to clearly separate scientific and engineering concerns in model and simulation development, and an argumentation approach to documenting models for rigorous way of recording assumptions and knowledge gaps. We propose interactive, dynamic visualisation tools to enable the biological community to interact with cellular signalling models directly for experimental design. There is a mismatch in scale between these cellular models and tissue structures that are affected by tumours, and bridging this gap requires substantial computational resource. We present concurrent programming as a technology to link scales without losing important details through model simplification. We discuss the value of combining this technology, interactive visualisation, argumentation and model separation to support development of multi-scale models that represent biologically plausible cells arranged in biologically plausible structures that model cell behaviour, interactions and response to therapeutic interventions

Conflict Detection for Edits on Extended Feature Models using Symbolic Graph Transformation

Feature models are used to specify variability of user-configurable systems as appearing, e.g., in software product lines. Software product lines are supposed to be long-living and, therefore, have to continuously evolve over time to meet ever-changing requirements. Evolution imposes changes to feature models in terms of edit operations. Ensuring consistency of concurrent edits requires appropriate conflict detection techniques. However, recent approaches fail to handle crucial subtleties of extended feature models, namely constraints mixing feature-tree patterns with first-order logic formulas over non-Boolean feature attributes with potentially infinite value domains. In this paper, we propose a novel conflict detection approach based on symbolic graph transformation to facilitate concurrent edits on extended feature models. We describe extended feature models formally with symbolic graphs and edit operations with symbolic graph transformation rules combining graph patterns with first-order logic formulas. The approach is implemented by combining eMoflon with an SMT solver, and evaluated with respect to applicability.Comment: In Proceedings FMSPLE 2016, arXiv:1603.0857