Mechanism of Cardiac Tropomyosin Transitions on Filamentous Actin As Revealed by All-Atom Steered Molecular Dynamics Simulations

Q: What is the clinical evidence from this study?

Population: Cardiac thin filament mechanics (tropomyosin transitions on filamentous actin). Intervention: Azimuthal transition pathway of tropomyosin across filamentous actin using steered molecular dynamics vs. Longitudinal and angled transition pathways of tropomyosin across filamentous actin. Primary outcome: Ensemble average work required per quasirepeat to transition tropomyosin from the blocked to the closed state.

Q: What does this research mean for the field?

Azimuthal motion of tropomyosin around filamentous actin requires lower total work than longitudinal or angled paths, making it the most probable transition mechanism from the blocked to the closed state. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Michael R. Williams; Jil C. Tardiff; Steven D. Schwartz

doi:10.1021/acs.jpclett.8b00958

June 4, 2018The Journal of Physical Chemistry LettersOpen Access

Mechanism of Cardiac Tropomyosin Transitions on Filamentous Actin As Revealed by All-Atom Steered Molecular Dynamics Simulations

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Key result

Azimuthal tropomyosin movement requires ~17% less work than longitudinal transitions during actin activation.

Key Points

To identify the most probable physical pathway and free-energy requirements for cardiac tropomyosin transitioning from the blocked state to the closed state on filamentous actin.
Modeled the cardiac thin filament using all-atom steered molecular dynamics (SMD) in NAMD 2.12 with the CHARMM 27 force field.
Simulated an ensemble of 10 runs containing two tropomyosin dimers to calculate the average work per quasirepeat across azimuthal, longitudinal, and angled trajectories.
Implemented two-stage SMD simulations with initial perpendicular pulling intervals between 10 ps and 50 ps to evaluate detachment from actin interactions.
The average equilibrium interaction energy per single quasirepeat in the full cardiac thin filament was measured to be 432 kcal/mol.
The azimuthal transition required the lowest total work of 1646.6 kcal/mol over a travel distance of 20.5 Å, despite presenting the highest initial energy barrier.
Longitudinal and angled pathways required 1985.1 kcal/mol across 37.5 Å and 2038.3 kcal/mol across 35.8 Å, respectively.

Structured PICO

P

Population

All-atom computational model of the cardiac thin filament (actin, tropomyosin, and cardiac troponin) evaluated across ensembles of 3 to 10 steered molecular dynamics simulations.

I

Intervention

Steered molecular dynamics (SMD) simulations pulling tropomyosin from the blocked state to the closed state via an azimuthal transition pathway (constant velocity of 0.0005 Å/fs without actin constraints, two-stage perpendicular pull of 10 or 25 ps at 0.0005 Å/fs, and slower velocity of 0.00005 Å/fs with 100 kcal/(mol·Å²) harmonic constraints on actin backbone atoms)

C

Comparator

Longitudinal and angled transition pathways of tropomyosin from the blocked state to the closed state across filamentous actin under identical SMD simulation protocols

O

Outcome

Total work (free energy per quasirepeat in kcal/mol) required to move the tropomyosin strand from the blocked position to the closed position on filamentous actin

Main Result

Absolute Event Rate: 1646.6% vs 1985.1%

All-atom steered molecular dynamics simulations demonstrate that cardiac tropomyosin most likely transitions from the blocked to the closed state on filamentous actin via an azimuthal rotational pathway rather than a longitudinal shift because the shorter path length requires less total work.

Limitations

Calculated numerical free energies are not expected to be exact, only showing relative likelihood of the paths studied.
Perpendicular pulls in two-stage simulations imposed artificial elongation on tropomyosin.
Cardiac troponin stayed stationary during the steered molecular dynamics simulations and did not contribute to the observed energy needed.
Only three individual simulations were conducted for each transition in the slower velocity method due to the increased computational time scale.
Calculated free energies are not expected to be exact numerical values, only showing relative likelihood of different pathways.
Two-stage perpendicular pulls imposed artificial elongation on tropomyosin.
Cardiac troponin remained stationary during simulations and its contribution to the energy needed was not observed.
Only three simulations per transition were conducted in the slower velocity method due to increased computational time scale.

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Implication

Azimuthal tropomyosin transition favored in simulations; hypothesis-generating for cardiac thin-filament regulation, no practice implications yet.

Abstract

The three-state model of tropomyosin (Tm) positioning along filamentous actin allows for Tm to act as a gate for myosin head binding with actin. The blocked state of Tm prevents myosin binding, while the open state allows for strong binding. Intermediate to this transition is the closed state. The details of the transition from the blocked to the closed state and then finally to the open state by Tm have not been fully accessible to experiment. Utilizing steered molecular dynamics, we investigate the work required to move the Tm strand through the extant set of proposed transitions. We find that an azimuthal motion around the actin filament by Tm is most probable in spite of increased initial energy barrier from the topographical landscape of actin.

Discussion

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Cite This Study

Williams et al. (2018) studied Cardiac thin filament mechanics (tropomyosin transitions on filamentous actin). Azimuthal transition pathway of tropomyosin across filamentous actin using steered molecular dynamics vs. Longitudinal and angled transition pathways of tropomyosin across filamentous actin was evaluated on Ensemble average work required per quasirepeat to transition tropomyosin from the blocked to the closed state. Azimuthal motion of tropomyosin around the actin filament required lower total work per quasirepeat than longitudinal or angled transitions.

synapsesocial.com/papers/6a8c17abdf3a83baf8cab709 https://doi.org/10.1021/acs.jpclett.8b00958

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Mechanism of Cardiac Tropomyosin Transitions on Filamentous Actin As Revealed by All-Atom Steered Molecular Dynamics Simulations

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Mechanism of Cardiac Tropomyosin Transitions on Filamentous Actin As Revealed by All-Atom Steered Molecular Dynamics Simulations

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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