How to build comprehensive models in systems biology: rules and principles of biological system modelling exemplified by molecular models of muscle contraction

Srba Mijailovich
Senior Research Scientist
Harvard School of Public Health


Using the methods of engineering and system-biology analysis, we are developing a computational platform that incorporates current knowledge of molecular structure, biochemical energetics, and contraction kinetics to describe muscle contraction. Our goal is to develop a comprehensive system biology model that can be used to (1) generate new mechanistic hypotheses concerning the functions of the contractile proteins myosin and actin and (2) quantitatively evaluate the roles of accessory and regulatory proteins in contraction. Once developed, the model will be a powerful analytical and predictive tool in studies of muscle contraction. Presently, no models of contraction account for complications due to both (1) extensibility of the actin and myosin filaments and (2) Ca2+ regulation of contraction. Filament extensibility results in non-uniform load transfer along the thick and thin filaments, which introduces variability in the stress and strain of the myosin heads during their interactions with actin. These effects must be taken into account to understand how cross-bridge forces affect chemical transitions in the actomyosin ATPase cycle and vice versa. Further, quantitative understanding of Ca2+ regulation will allow (1) more accurate predictions of the macroscopic mechanical and energetic consequences of specific regulatory events and (2) more accurate explanations of macroscopic events in terms of underlying molecular processes. These problems are addressed via a multidisciplinary approach that spans engineering science, computational science, and biophysics and rests entirely upon first principles. Our team is developing a model of contraction that integrates a critical missing element - filament extensibility - with recent advances in understanding the (1) biochemical states of myosin; (2) transitional rate constants in the actomyosin ATP hydrolysis cycle; (3) function of myosin molecular motors in the thick and thin filament lattice (sarcomere); and (4) Ca2+ regulation of myosin binding. Initially, the model will combine probabilistic or stochastic actomyosin binding kinetics with finite element analysis (either continuous or spatially discrete consistent with the periodicities of the thick and thin filaments). The model will then be refined to explain smooth muscle contraction, including the energetically efficient latch state and the actions of proteins involved in the regulation of contraction. The computational model developed here will invoke unifying principles that apply to the actomyosin interaction cycle regardless of muscle type but will have sufficient flexibility to account for contraction kinetics and regulation of contraction in different muscle types. Quantitative modeling of contraction is ultimately essential for understanding the molecular basis for a wide range of syndromes and diseases, such as airway narrowing in asthma and weakness of both heart and skeletal muscles in heart failure.


My current research focuses on the development of quantitative approaches to study biological systems at multiple levels of organization (i.e. multiscale modeling). In particular I am interested in developing a theoretical framework that will advance our understanding of how cellular and subcellular phenomena integrate to impact structure-function and dynamic relations of whole physiological systems, based on the kinetics of underlying molecular processes.

Our laboratory, established in fall 2003, focuses on the interplay between mechanical forces, cell biology, and integrated organ physiology. The central issues are: (1) how a cell actively develops mechanical forces, and how these forces affect chemical transitions (for example in the actomyosin ATPase cycle); (2) how a cell senses and responds to mechanical forces; and (3) how changes in protein-protein interactions of the cytoskeletal elements and accessory proteins inside the cell can affect cell or organ properties and their function.

We bring to this research area an interdisciplinary approach that spans engineering science, computational science, biology, biochemistry, and biophysics. We combine molecular, cellular, and whole organ approaches in order to understand cell and tissue biology, muscle physiology, and whole organ physiology. Pulmonary physiology and smooth muscle biology remain the core of our research experience, however, the interdisciplinary approach described in a recently awarded grant, can be expanded to the studies of the cardiovascular system and musculoskeletal disorders.

Principal topics of our research include: (1) Quantitative System Analysis of Muscle Mechanics and Metabolism; (2) In Vitro Test of a Critical Phenomenon Causing Airway Closure in Normals and Asthmatics; (3) "Virtual Sooth Muscle" Project; and (4) the Development of a "Virtual Lung".