title: Ising model of cardiac thin filament activation with nearest-neighbor cooperative interactions.
abstract: We have developed a model of cardiac thin filament activation using an Ising model approach from equilibrium statistical physics. This model explicitly represents nearest-neighbor interactions between 26 troponin/tropomyosin units along a one-dimensional array that represents the cardiac thin filament. With transition rates chosen to match experimental data, the results show that the resulting force-pCa (F-pCa) relations are similar to Hill functions with asymmetries, as seen in experimental data. Specifically, Hill plots showing (log(F/(1-F)) vs. log [Ca]) reveal a steeper slope below the half activation point (Ca(50)) compared with above. Parameter variation studies show interplay of parameters that affect the apparent cooperativity and asymmetry in the F-pCa relations. The model also predicts that Ca binding is uncooperative for low [Ca], becomes steeper near Ca(50), and becomes uncooperative again at higher [Ca]. The steepness near Ca(50) mirrors the steep F-pCa as a result of thermodynamic considerations. The model also predicts that the correlation between troponin/tropomyosin units along the one-dimensional array quickly decays at high and low [Ca], but near Ca(50), high correlation occurs across the whole array. This work provides a simple model that can account for the steepness and shape of F-pCa relations that other models fail to reproduce.
authors.affiliation: IBM T. J. Watson Research Center, Yorktown Heights, New York 10598, USA. johnrice@us.ibm.com
authors.forename: John Jeremy
authors.initials: JJ
authors.lastname: Rice
authors.forename: Gustavo
authors.initials: G
authors.lastname: Stolovitzky
authors.forename: Yuhai
authors.initials: Y
authors.lastname: Tu
authors.forename: Pieter P
authors.initials: PP
authors.lastname: de Tombe
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000502:physiology*; D003198:Computer Simulation; D046911:Macromolecular Substances; D008954:Models, Biological; D020409:Molecular Motor Proteins / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000502:physiology; D009210:Myofibrils / Q000502:physiology*; D011485:Protein Binding; D051381:Rats; D013314:Stress, Mechanical; D014335:Tropomyosin / Q000502:physiology; D014336:Troponin / Q000502:physiology
chemical_list: D046911:Macromolecular Substances; D020409:Molecular Motor Proteins; D014335:Tropomyosin; D014336:Troponin; D002118:Calcium