Computational modeling is emerging as a powerful new approach to study and manipulate biological systems. Multiple methods have been developed to model, visualize, and rationally alter systems at various length scales, starting from molecular modeling and design at atomic resolution to cellular pathways modeling and analysis. Higher time and length scale processes, such as molecular evolution, have also greatly benefited from new breeds of computational approaches. This book provides an overview of the established computational methods used for modeling biologically and medically relevant systems.

A practice-oriented survey of techniques for computational modeling and simulation suitable for a broad range of biological problems. There are many excellent computational biology resources now available for learning about methods that have been developed to address specific biological systems, but comparatively little attention has been paid to training aspiring computational biologists to handle new and unanticipated problems. This text is intended to fill that gap by teaching students how to reason about developing formal mathematical models of biological systems that are amenable to computational analysis. It collects in one place a selection of broadly useful models, algorithms, and theoretical analysis tools normally found scattered among many other disciplines. It thereby gives the aspiring student a bag of tricks that will serve him or her well in modeling problems drawn from numerous subfields of biology. These techniques are taught from the perspective of what the practitioner needs to know to use them effectively, supplemented with references for further reading on more advanced use of each method covered. The text, which grew out of a class taught at Carnegie Mellon University, covers models for optimization, simulation and sampling, and parameter tuning. These topics provide a general framework for learning how to formulate mathematical models of biological systems, what techniques are available to work with these models, and how to fit the models to particular systems. Their application is illustrated by many examples drawn from a variety of biological disciplines and several extended case studies that show how the methods described have been applied to real problems in biology.

How new modeling techniques can be used to explore functionally relevant molecular and cellular relationships.

I Principles 1 1 Models of Systems 3 1. 1 Systems. Models. and Modeling . . . . . . . . . . . . . . . . . . . . 3 1. 2 Uses of Scientific Models . . . . . . . . . . . . . . . . . . . . . . . . 4 1. 3 Example: Island Biogeography . . . . . . . . . . . . . . . . . . . . . 6 1. 4 Classifications of Models . . . . . . . . . . . . . . . . . . . . . . . . 10 1. 5 Constraints on Model Structure . . . . . . . . . . . . . . . . . . . . . 12 1. 6 Some Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 1. 7 Misuses of Models: The Dark Side . . . . . . . . . . . . . . . . . . . 13 1. 8 Exercises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 2 The Modeling Process 17 2. 1 Models Are Problems . . . . . . . . . . . . . . . . . . . . . . . . . . 17 2. 2 Two Alternative Approaches . . . . . . . . . . . . . . . . . . . . . . 18 2. 3 An Example: Population Doubling Time . . . . . . . . . . . . . . . . 24 2. 4 Model Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 2. 5 Exercises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 3 Qualitative Model Formulation 32 3. 1 How to Eat an Elephant . . . . . . . . . . . . . . . . . . . . . . . . . 32 3. 2 Forrester Diagrams . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 3. 3 Examples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 3. 4 Errors in Forrester Diagrams . . . . . . . . . . . . . . . . . . . . . . 44 3. 5 Advantages and Disadvantages of Forrester Diagrams . . . . . . . . . 44 3. 6 Principles of Qualitative Formulation . . . . . . . . . . . . . . . . . . 45 3. 7 Model Simplification . . . . . . . . . . . . . . . . . . . . . . . . . . 47 3. 8 Other Modeling Problems . . . . . . . . . . . . . . . . . . . . . . . . 49 viii Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. 9 Exercises 53 4 Quantitative Model Formulation: I 4. 1 From Qualitative to Quantitative . . . . . . . . . . . . . . . . . Finite Difference Equations and Differential Equations 4. 2 . . . . . . . . . . . . . . . . 4. 3 Biological Feedback in Quantitative Models . . . . . . . . . . . . . . . . . . . . . . . . . . 4. 4 Example Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. 5 Exercises 5 Quantitative Model Formulation: I1 81 . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. 1 Physical Processes 81 . . . . . . . . . . . . . . . 5. 2 Using the Toolbox of Biological Processes 89 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. 3 Useful Functions 96 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. 4 Examples 102 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. 5 Exercises 104 6 Numerical Techniques 107 . . . . . . . . . . . . . . . . . . . . . . . 6. 1 Mistakes Computers Make 107 . . . . . . . . . . . . . . . . . . . . . . . . . . 6. 2 Numerical Integration 110 . . . . . . . . . . . . . . . . 6. 3 Numerical Instability and Stiff Equations 115 . . . . . . . . . . . . . .

Emphasises a hands-on approach to modelling Strong emphasis on coding and software tools for systems biology Covers the entire spectrum of modelling, from static networks, to dynamic models Thoughtful exercises to test and enable student understanding of concepts Current chapters on exciting new developments like whole-cell modelling and community modelling

An introduction to the mathematical concepts and techniques needed for the construction and analysis of models in molecular systems biology. Systems techniques are integral to current research in molecular cell biology, and system-level investigations are often accompanied by mathematical models. These models serve as working hypotheses: they help us to understand and predict the behavior of complex systems. This book offers an introduction to mathematical concepts and techniques needed for the construction and interpretation of models in molecular systems biology. It is accessible to upper-level undergraduate or graduate students in life science or engineering who have some familiarity with calculus, and will be a useful reference for researchers at all levels. The first four chapters cover the basics of mathematical modeling in molecular systems biology. The last four chapters address specific biological domains, treating modeling of metabolic networks, of signal transduction pathways, of gene regulatory networks, and of electrophysiology and neuronal action potentials. Chapters 3–8 end with optional sections that address more specialized modeling topics. Exercises, solvable with pen-and-paper calculations, appear throughout the text to encourage interaction with the mathematical techniques. More involved end-of-chapter problem sets require computational software. Appendixes provide a review of basic concepts of molecular biology, additional mathematical background material, and tutorials for two computational software packages (XPPAUT and MATLAB) that can be used for model simulation and analysis.