Limits...
Dynamics and calcium association to the N-terminal regulatory domain of human cardiac troponin C: a multiscale computational study.

Lindert S, Kekenes-Huskey PM, Huber G, Pierce L, McCammon JA - J Phys Chem B (2012)

Bottom Line: Dynamics between the states are compared, and the Ca(2+)-bound system is investigated for opening motions.On the basis of the simulations, NMR chemical shifts and order parameters are calculated and compared with experimental observables.We furthermore indicate the essential role of electrostatic steering in facilitating diffusion-limited binding of Ca(2+).

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, NSF Center for Theoretical Biological Physics, National Biomedical Computation Resource, University of California San Diego, La Jolla, California 92093, United States. slindert@ucsd.edu

ABSTRACT
Troponin C (TnC) is an important regulatory molecule in cardiomyocytes. Calcium binding to site II in TnC initiates a series of molecular events that result in muscle contraction. The most direct change upon Ca(2+) binding is an opening motion of the molecule that exposes a hydrophobic patch on the surface allowing for Troponin I to bind. Molecular dynamics simulations were used to elucidate the dynamics of this crucial protein in three different states: apo, Ca(2+)-bound, and Ca(2+)-TnI-bound. Dynamics between the states are compared, and the Ca(2+)-bound system is investigated for opening motions. On the basis of the simulations, NMR chemical shifts and order parameters are calculated and compared with experimental observables. Agreement indicates that the simulations sample the relevant dynamics of the system. Brownian dynamics simulations are used to investigate the calcium association of TnC. We find that calcium binding gives rise to correlative motions involving the EF hand and collective motions conducive of formation of the TnI-binding interface. We furthermore indicate the essential role of electrostatic steering in facilitating diffusion-limited binding of Ca(2+).

Show MeSH

Related in: MedlinePlus

PCA plot comparing cMDand aMD trajectory sampling for the Ca2+-bound system.The principal component space generated byknown structures of TnC is shown along with molecular dynamics trajectoriesthat are projected into the first versus second principal componentspace of known TnC structures. (A) Projections of known pdb structuresare shown as filled circles. The NMR structures of 1AP4, 1SPY, and 1MXL are shown as filledgreen, red, and blue circles, respectively. (B) Projection of the 1AP4 cMD trajectory (fullblue circles) into the PC space is shown in density coloring wheredarker shades of blue indicate the more heavily sampled parts of thetrajectory. (C) Projection of the 1AP4 aMD trajectory (full blue circles) intothe PC space is shown in density coloring. (D) Projections of the 1AP4 cMD trajectory (fullred circles) and the 1AP4 aMD trajectory (full blue circles) into the PC space are shown indensity coloring, where darker shades of red and blue indicate themore heavily sampled parts of the trajectories. cMD and aMD trajectoriesoverlap with extended sampling for the accelerated method. Completeoverlap of most heavily sampled regions for the aMD trajectory withthe cMD trajectory suggests that cMD samples most of the statisticallyrelevant conformations for this system.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3405770&req=5

fig1: PCA plot comparing cMDand aMD trajectory sampling for the Ca2+-bound system.The principal component space generated byknown structures of TnC is shown along with molecular dynamics trajectoriesthat are projected into the first versus second principal componentspace of known TnC structures. (A) Projections of known pdb structuresare shown as filled circles. The NMR structures of 1AP4, 1SPY, and 1MXL are shown as filledgreen, red, and blue circles, respectively. (B) Projection of the 1AP4 cMD trajectory (fullblue circles) into the PC space is shown in density coloring wheredarker shades of blue indicate the more heavily sampled parts of thetrajectory. (C) Projection of the 1AP4 aMD trajectory (full blue circles) intothe PC space is shown in density coloring. (D) Projections of the 1AP4 cMD trajectory (fullred circles) and the 1AP4 aMD trajectory (full blue circles) into the PC space are shown indensity coloring, where darker shades of red and blue indicate themore heavily sampled parts of the trajectories. cMD and aMD trajectoriesoverlap with extended sampling for the accelerated method. Completeoverlap of most heavily sampled regions for the aMD trajectory withthe cMD trajectory suggests that cMD samples most of the statisticallyrelevant conformations for this system.

Mentions: PCAcharacterizes collective, high-amplitude structural variations basedon a set of homologous protein structures. The predominant modes providea basis for analyzing large-scale conformational changes anticipatedin MD simulations. In this study, NMR structures of apo-TnC, Ca2+-bound TnC, Ca2+/TnI-bound TnC, and TnC in complexwith compounds such as bepridil, W7, and dfbp were used as inputsfor PCA. The first two principal components, PC1 and PC2, are illustratedin Figure 1and account for 50.9 and 13.5%,respectively, of the variance associated with known TnC structures.As the two components together account for 64.4% of the variance,it was considered to be appropriate to analyze the simulations justin terms of these components. PC3 accounts for another 10.4% of thevariance but was not used for analysis because of its relatively lowcontribution. The quadrants along PC1 and PC2 describe apo and Ca2+-bound TnC structures (lower right, e.g., 1SPY, 1AP4) and Ca2+-TnI-bound TnC structures (left side, e.g., 1MXL, 2L1R).


Dynamics and calcium association to the N-terminal regulatory domain of human cardiac troponin C: a multiscale computational study.

Lindert S, Kekenes-Huskey PM, Huber G, Pierce L, McCammon JA - J Phys Chem B (2012)

PCA plot comparing cMDand aMD trajectory sampling for the Ca2+-bound system.The principal component space generated byknown structures of TnC is shown along with molecular dynamics trajectoriesthat are projected into the first versus second principal componentspace of known TnC structures. (A) Projections of known pdb structuresare shown as filled circles. The NMR structures of 1AP4, 1SPY, and 1MXL are shown as filledgreen, red, and blue circles, respectively. (B) Projection of the 1AP4 cMD trajectory (fullblue circles) into the PC space is shown in density coloring wheredarker shades of blue indicate the more heavily sampled parts of thetrajectory. (C) Projection of the 1AP4 aMD trajectory (full blue circles) intothe PC space is shown in density coloring. (D) Projections of the 1AP4 cMD trajectory (fullred circles) and the 1AP4 aMD trajectory (full blue circles) into the PC space are shown indensity coloring, where darker shades of red and blue indicate themore heavily sampled parts of the trajectories. cMD and aMD trajectoriesoverlap with extended sampling for the accelerated method. Completeoverlap of most heavily sampled regions for the aMD trajectory withthe cMD trajectory suggests that cMD samples most of the statisticallyrelevant conformations for this system.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3405770&req=5

fig1: PCA plot comparing cMDand aMD trajectory sampling for the Ca2+-bound system.The principal component space generated byknown structures of TnC is shown along with molecular dynamics trajectoriesthat are projected into the first versus second principal componentspace of known TnC structures. (A) Projections of known pdb structuresare shown as filled circles. The NMR structures of 1AP4, 1SPY, and 1MXL are shown as filledgreen, red, and blue circles, respectively. (B) Projection of the 1AP4 cMD trajectory (fullblue circles) into the PC space is shown in density coloring wheredarker shades of blue indicate the more heavily sampled parts of thetrajectory. (C) Projection of the 1AP4 aMD trajectory (full blue circles) intothe PC space is shown in density coloring. (D) Projections of the 1AP4 cMD trajectory (fullred circles) and the 1AP4 aMD trajectory (full blue circles) into the PC space are shown indensity coloring, where darker shades of red and blue indicate themore heavily sampled parts of the trajectories. cMD and aMD trajectoriesoverlap with extended sampling for the accelerated method. Completeoverlap of most heavily sampled regions for the aMD trajectory withthe cMD trajectory suggests that cMD samples most of the statisticallyrelevant conformations for this system.
Mentions: PCAcharacterizes collective, high-amplitude structural variations basedon a set of homologous protein structures. The predominant modes providea basis for analyzing large-scale conformational changes anticipatedin MD simulations. In this study, NMR structures of apo-TnC, Ca2+-bound TnC, Ca2+/TnI-bound TnC, and TnC in complexwith compounds such as bepridil, W7, and dfbp were used as inputsfor PCA. The first two principal components, PC1 and PC2, are illustratedin Figure 1and account for 50.9 and 13.5%,respectively, of the variance associated with known TnC structures.As the two components together account for 64.4% of the variance,it was considered to be appropriate to analyze the simulations justin terms of these components. PC3 accounts for another 10.4% of thevariance but was not used for analysis because of its relatively lowcontribution. The quadrants along PC1 and PC2 describe apo and Ca2+-bound TnC structures (lower right, e.g., 1SPY, 1AP4) and Ca2+-TnI-bound TnC structures (left side, e.g., 1MXL, 2L1R).

Bottom Line: Dynamics between the states are compared, and the Ca(2+)-bound system is investigated for opening motions.On the basis of the simulations, NMR chemical shifts and order parameters are calculated and compared with experimental observables.We furthermore indicate the essential role of electrostatic steering in facilitating diffusion-limited binding of Ca(2+).

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, NSF Center for Theoretical Biological Physics, National Biomedical Computation Resource, University of California San Diego, La Jolla, California 92093, United States. slindert@ucsd.edu

ABSTRACT
Troponin C (TnC) is an important regulatory molecule in cardiomyocytes. Calcium binding to site II in TnC initiates a series of molecular events that result in muscle contraction. The most direct change upon Ca(2+) binding is an opening motion of the molecule that exposes a hydrophobic patch on the surface allowing for Troponin I to bind. Molecular dynamics simulations were used to elucidate the dynamics of this crucial protein in three different states: apo, Ca(2+)-bound, and Ca(2+)-TnI-bound. Dynamics between the states are compared, and the Ca(2+)-bound system is investigated for opening motions. On the basis of the simulations, NMR chemical shifts and order parameters are calculated and compared with experimental observables. Agreement indicates that the simulations sample the relevant dynamics of the system. Brownian dynamics simulations are used to investigate the calcium association of TnC. We find that calcium binding gives rise to correlative motions involving the EF hand and collective motions conducive of formation of the TnI-binding interface. We furthermore indicate the essential role of electrostatic steering in facilitating diffusion-limited binding of Ca(2+).

Show MeSH
Related in: MedlinePlus