TY - JOUR
T1 - Free-Energy Surfaces of Two Cardiac Thin Filament Conformational Changes during Muscle Contraction
AU - Mason, Allison B.
AU - Tardiff, Jil C.
AU - Schwartz, Steven D.
N1 - Funding Information:
This research was supported by the National Institutes of Health (grant R01HL107046) to J.C.T. and S.D.S. All computer simulations were performed on a Lenovo NeXtScale nx360 M5 supercomputer at the University of Arizona High Performance Computing Center.
Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/6/2
Y1 - 2022/6/2
N2 - 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 Ca2+and cTnI dissociating from actin with both open and closed cTnC. These results not only provide the free-energy 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.
AB - 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 Ca2+and cTnI dissociating from actin with both open and closed cTnC. These results not only provide the free-energy 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.
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U2 - 10.1021/acs.jpcb.2c01337
DO - 10.1021/acs.jpcb.2c01337
M3 - Article
C2 - 35584206
AN - SCOPUS:85131269748
VL - 126
SP - 3844
EP - 3851
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
SN - 1520-6106
IS - 21
ER -