Computing Average Passive Forces in Sarcomeres in Length-Ramp Simulations

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dc.contributor.authorHerzog, Walter
dc.contributor.authorSchnappacher-Tilp, Gudrun
dc.contributor.authorLeonard, Timothy
dc.contributor.authorDesch, Gertrud
dc.date.accessioned2016-06-21T19:07:33Z
dc.date.available2016-06-21T19:07:33Z
dc.date.issued2016-06
dc.description.abstractPassive forces in sarcomeres are mainly related to the giant protein titin. Titin’s extensible region consists of spring-like elements acting in series. In skeletal muscles these elements are the PEVK segment, two distinct immunoglobulin (Ig) domain regions (proximal and distal), and a N2A portion. While distal Ig domains are thought to form inextensible end filaments in intact sarcomeres, proximal Ig domains unfold in a force- and time-dependent manner. In length-ramp experiments of single titin strands, sequential unfolding of Ig domains leads to a typical saw-tooth pattern in force-elongation curves which can be simulated by Monte Carlo simulations. In sarcomeres, where more than a thousand titin strands are arranged in parallel, numerous Monte Carlo simulations are required to estimate the resultant force of all titin filaments based on the non-uniform titin elongations. To simplify calculations, the stochastic model of passive forces is often replaced by linear or non-linear deterministic and phenomenological functions. However, new theories of muscle contraction are based on the hypothesized binding of titin to the actin filament upon activation, and thereby on a prominent role of the structural properties of titin. Therefore, these theories necessitate a detailed analysis of titin forces in ength-ramp experiments. In our study we present a simple and efficient alternative to Monte Carlo simulations. Based on a structural titin model, we calculate the exact probability distributions of unfolded Ig domains under length-ramp conditions needed for rigorous analysis of expected forces, distribution of unfolding forces, etc. Due to the generality of our model, the approach is applicable to a wide range of stochastic protein unfolding problems.en_US
dc.description.refereedYesen_US
dc.description.sponsorshipAustrian Science Fund (FWF), grant number T478-N13; Canada Research Chair; Killam Foundation; Natural Sciences and Engineering Research Council of Canada; and the Canadian Insitutes of Health Research.en_US
dc.identifier.citationSchappacher-Tilp, G., Leonard, T., Desch, G., & Herzog, W. (2016). Computing Average Passive Forces in Sarcomeres in Length-Ramp Simulations. PLOS Comput Biol, 12(6), e1004904.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/29055
dc.identifier.urihttp://hdl.handle.net/1880/51404
dc.language.isoenen_US
dc.publisherPLOS Computational Biologyen_US
dc.publisher.departmentHuman Performance Laboratoryen_US
dc.publisher.facultyKinesiologyen_US
dc.publisher.institutionUniversity of Calgaryen_US
dc.subjectsarcommeresen_US
dc.subjectmuscleen_US
dc.subjectprotein titinen_US
dc.titleComputing Average Passive Forces in Sarcomeres in Length-Ramp Simulationsen_US
dc.typejournal article
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