? Using the methods of engineering analysis, we will develop 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 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 Ca 2+ 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. This BRP addresses these problems via a multidisciplinary approach that spans engineering science, computational science, and biophysics and rests entirely upon first principles. Our team will develop 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) Ca 2+ 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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR048776-04
Application #
7064230
Study Section
Special Emphasis Panel (ZRG1-SSS-M (03))
Program Officer
Nuckolls, Glen H
Project Start
2003-09-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$562,032
Indirect Cost
Name
Harvard University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Mijailovich, Srbolujub M; Nedic, Djordje; Svicevic, Marina et al. (2017) Modeling the Actin.myosin ATPase Cross-Bridge Cycle for Skeletal and Cardiac Muscle Myosin Isoforms. Biophys J 112:984-996
Mijailovich, Srboljub M; Kayser-Herold, Oliver; Stojanovic, Boban et al. (2016) Three-dimensional stochastic model of actin-myosin binding in the sarcomere lattice. J Gen Physiol 148:459-488
Prodanovic, Momcilo; Irving, Thomas C; Mijailovich, Srboljub M (2016) X-ray diffraction from nonuniformly stretched helical molecules. J Appl Crystallogr 49:784-797
Mijailovich, Srboljub M; Li, Xiaochuan; Griffiths, R Hugh et al. (2012) The Hill model for binding myosin S1 to regulated actin is not equivalent to the McKillop-Geeves model. J Mol Biol 417:112-28
Mijailovich, Srboljub M; Kayser-Herold, Oliver; Li, Xiaochuan et al. (2012) Cooperative regulation of myosin-S1 binding to actin filaments by a continuous flexible Tm-Tn chain. Eur Biophys J 41:1015-32
Geeves, Michael; Griffiths, Hugh; Mijailovich, Srboljub et al. (2011) Cooperative [Ca┬▓+]-dependent regulation of the rate of myosin binding to actin: solution data and the tropomyosin chain model. Biophys J 100:2679-87
Mijailovich, Srboljub M; Stojanovic, Boban; Kojic, Milos et al. (2010) Derivation of a finite-element model of lingual deformation during swallowing from the mechanics of mesoscale myofiber tracts obtained by MRI. J Appl Physiol 109:1500-14
Mijailovich, Srboljub M; Li, Xiaochuan; del Alamo, Juan C et al. (2010) Resolution and uniqueness of estimated parameters of a model of thin filament regulation in solution. Comput Biol Chem 34:19-33
Mijailovich, S M; Kojic, M; Tsuda, A (2010) Particle-induced indentation of the alveolar epithelium caused by surface tension forces. J Appl Physiol 109:1179-94
Alencar, Adriano M; Butler, James P; Mijailovich, Srboljub M (2009) Thermodynamic origin of cooperativity in actomyosin interactions: the coupling of short-range interactions with actin bending stiffness in an Ising-like model. Phys Rev E Stat Nonlin Soft Matter Phys 79:041906

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