Agent-Based Modeling of Complex Molecular Systems.

The seamless integration of laboratory experiments and detailed computational modeling provides an exciting route to uncovering many new insights into complex biological processes. In particular, the development of agent-based modeling using supercomputers has provided new opportunities for highly detailed, validated simulations that provide the researcher with greater understanding of these processes and new directions for investigation. This chapter examines some of the principles behind the powerful computational framework FLAME and its application in a number of different areas with a more detailed look at a particular signaling example involving the NF-κB cascade.

Distinct Binding Interactions of αβ-Integrin and Proteoglycans with Fibronectin.

Dynamic single-molecule force spectroscopy was performed to monitor the unbinding of fibronectin with the proteoglycans syndecan-4 (SDC4) and decorin and to compare this with the unbinding characteristics of αβ-integrin. A single energy barrier was sufficient to describe the unbinding of both SDC4 and decorin from fibronectin, whereas two barriers were observed for the dissociation of αβ-integrin from fibronectin. The outer (high-affinity) barriers in the interactions of fibronectin with αβ-integrin and SDC4 are characterized by larger barrier heights and widths and slower dissociation rates than those of the inner (low-affinity) barriers in the interactions of fibronectin with αβ-integrin and decorin.

The IL-1RI Co-Receptor TILRR ( Isoform 2) Controls Aberrant Inflammatory Responses and Development of Vascular Disease.

Expression of the interleukin-1 receptor type I (IL-1RI) co-receptor Toll-like and interleukin-1 receptor regulator (TILRR) is significantly increased in blood monocytes following myocardial infarction and in the atherosclerotic plaque, whereas levels in healthy tissue are low. TILRR association with IL-1RI at these sites causes aberrant activation of inflammatory genes, which underlie progression of cardiovascular disease. The authors show that genetic deletion of TILRR or antibody blocking of TILRR function reduces development of atherosclerotic plaques.

Statistical Techniques Complement UML When Developing Domain Models of Complex Dynamical Biosystems.

Computational modelling and simulation is increasingly being used to complement traditional wet-lab techniques when investigating the mechanistic behaviours of complex biological systems. In order to ensure computational models are fit for purpose, it is essential that the abstracted view of biology captured in the computational model, is clearly and unambiguously defined within a conceptual model of the biological domain (a domain model), that acts to accurately represent the biological system and to document the functional requirements for the resultant computational model. We present a domain model of the IL-1 stimulated NF-κB signalling pathway, which unambiguously defines the spatial, temporal and stochastic requirements for our future computational model.

Reducing complexity in an agent based reaction model-Benefits and limitations of simplifications in relation to run time and system level output.

Agent based modelling is a methodology for simulating a variety of systems across a broad spectrum of fields. However, due to the complexity of the systems it is often impossible or impractical to model them at a one to one scale. In this paper we use a simple reaction rate model implemented using the FLAME framework to test the impact of common methods for reducing model complexity such as reducing scale, increasing iteration duration and reducing message overheads.