Role of Theory, Modelling and Simulation in Biomedicine
Invited Speakers
Prof Tom McLeish, University of York
Prof Mike Dustin, University of Oxford
Symposium Co-Chairs
Erik Lindahl, Professor of Biophysics
Andrea Townsend-Nicholson, Professor of Biochemistry & Molecular Biology
Symposium Description
The life sciences, and particularly medicine, are often regarded as highly empirical in nature. To this day, established journals in these domains actively pursue a policy by which publication of theoretical ideas and methods is encouraged solely when used to rationalise previously obtained experimental results. As a result, computational modelling is primarily used a posteriori to explain quantitative measurements obtained by experimental biologists. The notion that theories and models can be used in a genuinely predictive fashion, and are worth publishing in their own right and before experimental work is performed, is not widely held.
This approach is in dramatic contrast with how the physical sciences work today. However, the whole purpose of personalised medicine is the explicit use of theory and modelling to make predictions of an individual’s response to a drug or to a surgical intervention that are of sufficient fidelity that they can be used for clinical decision making. In this symposium, we shall look at the reasons for scepticism toward theory in the life sciences, provide examples of the successful use of theory in this domain, and discuss ways in which the credibility of theory, modelling and simulation can be enhanced through new approaches to education and training in biomedicine.
We have previously published agent-based models for the immune synapse1,2. The first generation model focused on development of the bull’s eye pattern generated by a system with small (~13 nm) TCR-ligand complexes, which are transported towards the central supramolecular activation cluster (cSMAC) and accumulate there, and large (>20 nm) LFA-1-ICAM-1 complexes that provide a “back-fill” of adhesion in the peripheral SMAC (pSMAC)1. The second generation incorporated a weak central transport for LFA-1-ICAM-1, enabling formation of a realistic radial distribution of interactions in the pSMAC2. Furthermore, we incorporated CD28-CD80 complexes, which are less abundant than LFA-1-ICAM-1 complexes and are the same size as the TCR-ligand complexes and thus could passively follow TCR-ligand complexes toward the center2. Full Abstract
Whole blood is a suspension of cells, red blood cells (RBCs), platelets, and white blood cells, in a protein rich plasma that collectively has a non-Newtonian rheology. RBCs are the most numerous blood cells and due to their deformability and bi-concave shape the RBC contributes significantly to the complex rheology of whole blood. Pathologies have been found to affect the deformability of the red blood cell such as Diabetes, Sickle Cell Anemia [1], and HIV. In this research we perform numerical and experimental analysis on the effects and outcomes of the presence of stiffened RBCs on haematocrit profiles and platelet margination in flowing whole blood. Full Abstract
13:40
Shunzhou Wan
Accurate, Precise and Reliable Binding Affinity Predictions for G Protein Coupled Receptors
There is an urgent need in the pharmaceutical industry for approaches and tools that are able to accurately, rapidly predict binding affinity values. Previous work[1-2] has demonstrated the inability of ‘one-off’ simulations to accurately, reliably and reproducibly predict the overall conformational states and dynamics of biological systems over a finite period of time. Thus, the use of enhanced sampling techniques is essential for accurate descriptions of binding between a receptor and its ligands. We investigate the application of Enhanced Sampling of Molecular Dynamics with Approximation of Continuum Solvent (ESMACS), and Thermodynamic Integration with Enhanced Sampling (TIES) for computing the binding affinities (see Figure 1) of a series of experimentally verifiable ligands to the A1 and A2A adenosine receptors (see Figure 2), members of a subclass of the GPCR superfamily.
. Full Abstract
13:55
Tom McLeish
(Invited Speaker)
The Noisy Physics of Protein Signalling: Global Low Frequency Protein Motions in Allosteric Binding
We present a theory and predictive methdology for how protein allostery can recruit modulation of low frequency dynamics without a change in protein structure [1]. Elastic inhomogeneities allow entropic ‘signalling at a distance’. Through multi-scale modelling of global normal modes we demonstrate negative co-operativity between the two cAMP ligands in CRP/FNR family allostery (fig. 1), without change to the mean structure. Crucially, the value of the co- operativity is itself controlled by the interactions around a set of third Figure 1 CAP protein featuring fluctuation-allosteric control sites calculated in an ENM formalism allosteric ‘control sites’. The theory makes key experimental predictions, validated by analysis of structure and isothermal calorimetry of variant proteins. Furthermore, we found that evolutionary selection pressure to conserve residues crucial for allosteric control [3]. The methodology establishes the means to engineer allosteric mechanisms that are driven by low frequency dynamics, and also suggests a programme of fundamental questions in thermally excited elastic matter [4], including control of biofilament self-assembly [5]. Full Abstract
