Dynamics and Calcium Association to the N-Terminal Regulatory Domain of Human Cardiac Troponin C: A Multiscale Computational Study

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 Ca2+ 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, Ca2+-bound, and Ca2+-TnI-bound. Dynamics between the states are compared, and the Ca2+-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 Ca2+.

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

“…The opening involves movement of the BC helices as a unit away from the NAD helices unit. MD simulations have detected a concerted tilting motion of helices B and C away from helix A, corresponding to the opening motion of cNTnC•Ca 2+ 75 . NMR amide proton relaxation dispersion experiments reveal that many residues in the hinge regions of cNTnC experience a conformational exchange process with a time scale of ~30 µs 76,77 .…”

Hybrid finite element and Brownian dynamics method for diffusion-controlled reactions

“…[17][18][19][20] One system of great interest is that of calcium ion diffusion in the cardiac myocyte, 4, 5, 33 the diffusion domain can be constructed from light and electron microscopy data, 33 while the calcium transporters and receptors can included in atomic detail for Brownian dynamics. 34 Other systems of interest include diffusion of acetylcholine in the neuromuscular junction [6][7][8][9] and the diffusion of sodium and potassium ions in the node of Ranvier. 10 Because such systems have multiple length and time scales, hybrid methods that can combine different algorithms and take advantage of their respective strengths will be useful for predicting and studying physiologically significant rates, fluxes, and currents.…”

Molecular Effects of cTnC DCM Mutations on Calcium Sensitivity and Myofilament Activation—An Integrated Multiscale Modeling Study

“…The initial preparation of the systems, including introduction of mutations, is described in 15–16 . The Ca 2+ -bound cTnC and cTnC-G159D systems contained three bound Ca 2+ ions (one in N-terminal lobe and two in C-terminal lobe).…”

“…Similar to studies presented in 16 , Brownian dynamics simulations were performed with BrownDye 30 to estimate calcium association rates. PQR files for representative protein structures determined by a cluster analysis were generated using pdb2pqr 31 .…”