Long-timescale molecular dynamics simulations elucidate the dynamics and kinetics of exposure of the hydrophobic patch in troponin C.
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 it an important target for studies investigating the detailed molecular processes that underlie contraction. Here we use microsecond-timescale Anton molecular dynamics simulations to investigate the dynamics and kinetics of the opening transition of the TnC hydrophobic patch. Free-energy differences for opening are calculated for wild-type Ca(2+)-bound TnC (∼8 kcal/mol), V44Q Ca(2+)-bound TnC (3.2 kcal/mol), E40A Ca(2+)-bound TnC (∼12 kcal/mol), and wild-type apo TnC (∼20 kcal/mol). These results suggest that the mutations have a profound impact on the frequency with which the hydrophobic patch presents to TnI. In addition, these simulations corroborate that cardiac wild-type TnC does not open on timescales relevant to contraction without calcium being bound.
Department of Pharmacology, University of California San Diego, La Jolla, California, USA. slindert@ucsd.edu
Steffen
S
Lindert
Peter M
PM
Kekenes-Huskey
J Andrew
JA
McCammon
D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D032383:Myocytes, Cardiac / Q000737:chemistry; D017434:Protein Structure, Tertiary; D019209:Troponin C / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D019209:Troponin C; D002118:Calcium