Free-Energy Surfaces of Two Cardiac Thin Filament Conformational Changes during Muscle Contraction

Abstract

The troponin core is an important regulatory complex in cardiac sarcomeres. Contraction is initiated by a calcium ion binding to cardiac troponin C (cTnC), initiating a conformational shift within the protein, altering its interactions with cardiac troponin I (cTnI). The change in cTnC−cTnI interactions prompts the C-terminal domain of cTnI to dissociate from actin, allowing tropomyosin to reveal myosin-binding sites on actin. Each of the concerted movements in the cardiac thin filament (CTF) is crucial for allowing the contraction of cardiomyocytes, yet little is known about the free energy associated with each transition, which is vital for understanding contraction on a molecular level. Using metadynamics, we calculated the free-energy surface of two transitions in the CTF: cTnC opening in the presence and absence of Ca 2+ and cTnI dissociating from actin with both open and closed cTnC. These results not only provide the freeenergy surface of the transitions but will also be shown to determine if the order of transitions in the contraction cycle is important. From our calculations, we found that the calcium ion helps stabilize the open conformation of cTnC and that the C-terminus of cTnI is stabilized by cTnC in the open conformation when dissociating from the actin surface.

Ryanodine receptor‐associated myopathies: What's myosin got to do with it?

“…selected two of the phosphorylated residues in the MYH7 polypeptide (Ser1362 in RYR1‐CM and Tyr1375 in both RYR1‐CM and RYR1‐RM) for closer examination using molecular dynamics (MD) simulations. MD has been widely used to examine molecular processes that are challenging, if not impossible to assess in muscle with current experimental approaches 11,15–19 . Dynamic simulations of portions of MYH7 rod suggest that phosphorylation could negatively impact structural dynamics of the rod—and by implication the thick filament backbone and interaction with IHM—in myopathy patients.…”

“…MD has been widely used to examine molecular processes that are challenging, if not impossible to assess in muscle with current experimental approaches. 11,[15][16][17][18][19] Dynamic simulations of portions of MYH7 rod suggest that phosphorylation could negatively impact structural dynamics of the rod-and by implication the thick filament backbone and interaction with IHM-in myopathy patients.…”

Remotely Controlled Light/Electric/Magnetic Multiresponsive Hydrogel for Fast Actuations

“…In nature, there are many interesting phenomena, such as mimosa being stimulated to close their leaves and chameleon changing its colors according to the external environment, which have inspired people to explore and study intelligent materials. Hydrogel, as a kind of soft intelligent material, − can convert external energy (light, − heat, , magnetic, , ion, − electrical, , chemical energy, − pH, − etc.) into its own mechanical energy, thus causing its own deformation (shrinking, swelling, spiraling, bending, etc.)…”

Umbrella Sampling Simulations of Cardiac Thin Filament Reveal Thermodynamic Consequences of Troponin I Inhibitory Peptide Mutations

“…Their successive molecular dynamics (MD) simulations utilizing this model were able to elucidate functional mechanisms for the cTn complex and potential causes of disease for cTnT mutations. , Recently, using cryogenic electron microscopy (cryo-EM), Yamada and colleagues resolved the structure of the cTn complex in the context of the thin filament for the first time in both the Ca 2+ -bound and Ca 2+ -unbound states . These structures have enabled computational studies to further understand the dynamics and function of cTn within the thin filament, a more physiologically relevant context than simulated isolated cTn . We have previously studied the thermodynamics of the cTn complex in isolation using a combination of targeted MD (TMD) and umbrella sampling (US) and were able to produce results that correlated with experimental and computational studies.…”

“…40 These structures have enabled computational studies to further understand the dynamics and function of cTn within the thin filament, a more physiologically relevant context than simulated isolated cTn. 41 We have previously studied the thermodynamics of the cTn complex in isolation using a combination of targeted MD (TMD) and umbrella sampling (US) 15 and were able to produce results that correlated with experimental 42 and computational 43 studies. However, these simulations were unable to explore the effect that actin would have on both the cTnI SP -binding and cTnC HP -opening events.…”