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Numerous selective estrogen receptor modulators (SERMs) have been synthesized and assayed in recent years. The focus of this study is to apply coarse-grain molecular docking procedures coupled with fine-grain all-atom force field optimization strategies to shed light on the binding mechanisms of currently available estrogen receptor-active compounds.(More)
Troponin (Tn) is an important regulatory protein in the thin-filament complex of cardiomyocytes. Calcium binding to the troponin C (TnC) subunit causes a change in its dynamics that leads to the transient opening of a hydrophobic patch on TnC's surface, to which a helix of another subunit, troponin I (TnI), binds. This process initiates contraction, making(More)
Triggered release of Ca2+ from an individual sarcoplasmic reticulum (SR) Ca(2+) release unit (CRU) is the fundamental event of cardiac excitation–contraction coupling, and spontaneous release events (sparks) are the major contributor to diastolic Ca(2+) leak in cardiomyocytes. Previous model studies have predicted that the duration and magnitude of the(More)
We report the 3D structure predicted for the mouse MrgC11 (mMrgC11) receptor by using the MembStruk computational protocol, and the predicted binding site for the F-M-R-F-NH(2) neuropeptide together with four singly chirally modified ligands. We predicted that the R-F-NH(2) part of the tetrapeptide sticks down into the protein between the transmembrane (TM)(More)
During β-adrenergic stimulation, cardiac troponin I (cTnI) is phosphorylated by protein kinase A (PKA) at sites S23/S24, located at the N-terminus of cTnI. This phosphorylation has been shown to decrease KCa and pCa50, and weaken the cTnC-cTnI (C-I) interaction. We recently reported that phosphorylation results in an increase in the rate of early, slow(More)
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(More)
Contractile function of cardiac cells is driven by the sliding displacement of myofilaments powered by the cycling myosin crossbridges. Critical to this process is the availability of ATP, which myosin hydrolyzes during the cross-bridge cycle. The diffusion of adenine nucleotides through the myofilament lattice has been shown to be anisotropic, with slower(More)
The sarcoplasmic reticulum Ca²⁺ ATPase (SERCA) is a membrane-bound pump that utilizes ATP to drive calcium ions from the myocyte cytosol against the higher calcium concentration in the sarcoplasmic reticulum. Conformational transitions associated with Ca²⁺-binding are important to its catalytic function. We have identified collective motions that partition(More)
To help improve the accuracy of protein-ligand docking as a useful tool for drug discovery, we developed MPSim-Dock, which ensures a comprehensive sampling of diverse families of ligand conformations in the binding region followed by an enrichment of the good energy scoring families so that the energy scores of the sampled conformations can be reliably used(More)
Cardiac troponin (cTn) is a key molecule in the regulation of human cardiac muscle contraction. The N-terminal cardiac-specific peptide of the inhibitory subunit of troponin, cTnI (cTnI(1-39)), is a target for phosphorylation by protein kinase A (PKA) during β-adrenergic stimulation. We recently presented evidence indicating that this peptide interacts with(More)