Catalyzing Inquiry at the Interface of Computing and Biology

COMPUTATIONAL MODELING AND SIMULATION AS ENABLERS FOR BIOLOGICAL DISCOVERY 165

Box 5.12

Examples of Intersection Between Structurally and Functionally Integrated Models

There are a number of examples of intersection between structurally and functionally integrated models,

including the following:

• Linkage of biochemical networks and spatially coupled processes, such as calcium diffusion in structurally
  based models of cell biophysics;^1


• Use of physicochemical constraints to optimize genomic systems models of cell metabolism;^2


• Integration of genomic or cellular system models into multicellular network models of memory and learn-
  ing,^3 developmental pattern formation,^4 or action potential propagation;^5


• Integration of structure-based predictions of protein function into systems models of molecular networks;


• Development of kinetic models of cell signaling and coupling them to physiological targets such as energy
  metabolism, ionic currents or cell motility;^6


• Use of empirical constraints to optimize protein folding predictions;^7 and


• Integration of systems models of cell dynamics into continuum models of tissue and organ physiology.^8

(^1) L.M. Loew, “The Virtual Cell Project,” Novartis Foundation Symposium 247:151-161, 2002; L.M. Loew and J.C. Schaff, “The Virtual Cell:
A Software Environment for Computational Cell Biology,” Trends in Biotechnology 19(10):401-406, 2001.
(^2) B.O. Palsson, “What Lies Beyond Bioinformatics?” Nature Biotechnology 15:3-4, 1997; C.H. Schilling, J.S. Edwards, D. Letscher, and
B.O. Palsson, “Combining Pathway Analysis with Flux Balance Analysis for the Comprehensive Study of Metabolic Systems,” Biotechnology
and Bioengineering 71(4):286-306, 2000-2001.
(^3) D. Durstewitz, J.K. Seamans, and T.J. Sejnowski, “Neurocomputational Models of Working Memory,” Nature Neuroscience
3(Supplement):S1184-S1191, 2000; P.H. Tiesinga, J.M. Fellous, J.V. Jose, and T.J. Sejnowski, “Information Transfer in Entrained Cortical
Neurons,” Network: Computation in Neural Systems 13(1):41-66, 2002.
(^4) E.H. Davison, J.P. Rast, P. Oliveri, A. Ransick, C. Calestani, C.H. Yuh, T. Minokawa, et al., “A Genomic Regulatory Network for
Development,” Science 295(5560):1669-1678, 2002.
(^5) R.M. Shaw and Y. Rudy, “Electrophysiologic Effects of Acute Myocardial Ischemia: A Mechanistic Investigation of Action Potential
Conduction and Conduction Failure,” Circulation Research 80(1):124-138, 1997.
(^6) J.M. Levin, R.C. Penland, A.T. Stamps, and C.R. Cho, “Using in Silico Biology to Facilitate Drug Development.,” in Novartis Foundation
Symposium 247: 222-238, 2002.
(^7) L. Salwinski and D. Eisenberg, “Motif-based Fold Assignment,” Protein Science 10(12):2460-2469, 2001.
(^8) R.L. Winslow, D.F. Scollan, A. Holmes, C.K. Yung, J. Zhang, M.S. Jafri, “Electrophysiological Modeling of Cardiac Ventricular Function:
From Cell to Organ,” Annual Reviews of Biomedical Engineering 2: 119-155, 2002; N.P. Smith, P.J. Mulquiney, M.P. Nash, C.P. Bradley,
D.P. Nickerson, and P.J. Hunter, “Mathematical Modelling of the Heart: Cell to Organ,” Chaos, Solitons and Fractals 13:1613-1621, 2002.
SOURCE: A.D. McCulloch and G. Huber, “Integrative Biological Modelling in Silico,” pp. 4-19 in ‘In Silico’ Simulation of Biological
Processes No. 247, Novartis Foundation Symposium, G. Bock and J.A. Goode, eds., John Wiley & Sons Ltd., Chichester, UK, 2002.
Reproduced with permission from John Wiley & Sons Ltd.
(^1) F.J. Vetterand A.D. McCulloch, “Three-dimensional Analysis of Regional Cardiac Function: A Model of Rabbit Ventricular Anatomy,”
Progress in Biophysics and Molecular Biology 69(2-3):157-183, 1998.
(^2) K. May-Newman and A.D. McCulloch, “Homogenization Modelling for the Mechanics of Perfused Myocardium,” Progress in Biophysics
and Molecular Biology 69(2-3):463-481, 1998.
(^3) T.P. Usyk, J.H. Omens, and A.D. McCulloch, “Regional Septal Dysfunction in a Three-dimensional Computational Model of Focal
Myofiber Disarray,” American Journal of Physiology 281(2):H506-H514, 2001.
(^4) L.J. Leon and F.A. Roberge, “Directional Characteristics of Action Potential Propagation in Cardiac Muscle: A Model Study,” Circulation
Research 69: 378-395, 1991.
SOURCE: Adapted from A.D. McCulloch and G. Huber, “Integrative Biological Modelling in Silico,” pp. 4-25 in ‘In Silico’ Simulation of
Biological Processes No. 247, Novartis Foundation Symposium, G. Bock and J.A. Goode, eds., John Wiley & Sons Ltd., Chichester, UK,
2002.