[MOS] 11/5 - Modern Optics and Spectroscopy Seminar with Yale Goldman (Penn)

[Christine Brooks]

There will be a Modern Optics and Spectroscopy Seminar held next Tuesday, November 5 in 34-401A<http://whereis.mit.edu/?go=34> at 12pm

Yale E. Goldman
University of Pennsylvania

“Ultra-Fast Single Molecule Mechanics Resolves the Earliest Events in Force Generation by Cardiac Myosin”

Key steps of cardiac mechanochemistry, including force generation via a working stroke and the release of phosphate (Pi), occur rapidly after myosin attaches to actin. The order and timing of these events has been controversial partly because of insufficient time resolution for detection of myosin binding to actin and direct observation of the mechanical impulse. An ultra-high-speed, optical trap technique, improving the detection speed some 50-fold, enabled direct observation of the timing and amplitude of the working stroke, showing the stroke can occur within <200 µs of actin binding by ß-cardiac myosin. The initial actomyosin state in the short period before the working stroke can sustain loads up to at least 4.5 pN and either proceeds directly to the stroke or detaches without binding ATP. The stroke time is not affected by the presence of 10 mM free Pi and other results indicate that the working stroke precedes release of phosphate. Pi can bind and reverse the working stroke at a later step helping to explain rapid fatigue in ischemic myocardium and heavily loaded skeletal muscle. Detection of these rapid events while actomyosin experiences realistic mechanical loads provides definitive indication of the reaction dynamics in myosin which convert biochemical energy into mechanical work and provide insight into the long-standing question of the detailed order of events in myosin energy transduction. We also used optical trap to determine how cardiac myosin is affected by omecamtiv mercarbil (OM), a new drug in clinical trials for heart failure. Our experiments reveal that, surprisingly, OM inhibits the myosin power stroke and prolongs actin attachment at saturating ATP concentrations. We show, using a simple computational model, how these effects can explain the seemingly contradictory results that OM helps patients, but it suppresses velocity in an in vitro actin gliding assay.


Refreshments will be served immediately following the seminar!


Christine Brooks
Administrative Assistant
Massachusetts Institute of Technology
Department of Chemistry
77 Massachusetts Ave, 6-333
Cambridge, MA 02139
p: 617.253.7239
e: cbrooks at mit.edu<mailto:cbrooks at mit.edu>

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