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<p class="MsoNormal"><span style="font-size:15.0pt">There will be a Modern Optics and Spectroscopy Seminar held next<b> Tuesday, November 5
</b>in <b><a href="http://whereis.mit.edu/?go=34">34-401A</a> at 12pm</b></span><o:p></o:p></p>
<p class="MsoNormal"><b><span style="font-size:14.0pt;color:red"> </span></b><b><span style="font-size:14.0pt"> </span></b><o:p></o:p></p>
<p class="MsoNormal" style="layout-grid-mode:char"><b><span style="font-size:18.0pt">Yale E. Goldman</span></b><b><span style="font-size:17.0pt"><br>
University of Pennsylvania</span></b><i><span style="font-size:14.0pt"><br>
<br>
</span></i><b><span style="font-size:18.0pt">“</span></b><b><span style="font-size:18.0pt">Ultra-Fast Single Molecule Mechanics Resolves the Earliest Events in Force Generation by Cardiac Myosin”</span></b><b><span style="font-size:18.0pt"><o:p></o:p></span></b></p>
<p class="MsoNormal" style="text-indent:.25in"><span style="font-size:18.0pt"><br>
</span><i><span style="mso-fareast-language:ZH-CN">Key steps of cardiac mechanochemistry, including force generation via a working stroke and the release of phosphate (P<sub>i</sub>), 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 P<sub>i</sub> and other results indicate that the working stroke precedes release of phosphate. P<sub>i</sub>
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.
<o:p></o:p></span></i></p>
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<p class="MsoNormal"><span style="font-size:14.0pt">Refreshments will be served immediately following the seminar!</span><o:p></o:p></p>
<p class="MsoNormal"><span style="font-size:11.0pt"> </span><o:p></o:p></p>
<p class="MsoNormal"><span style="font-size:11.0pt"> </span><o:p></o:p></p>
<p class="MsoNormal"><b><span style="font-size:11.0pt">Christine Brooks</span></b><o:p></o:p></p>
<p class="MsoNormal"><span style="font-size:11.0pt">Administrative Assistant</span><o:p></o:p></p>
<p class="MsoNormal"><span style="font-size:11.0pt">Massachusetts Institute of Technology</span><o:p></o:p></p>
<p class="MsoNormal"><span style="font-size:11.0pt">Department of Chemistry</span><o:p></o:p></p>
<p class="MsoNormal"><span style="font-size:11.0pt">77 Massachusetts Ave, 6-333</span><o:p></o:p></p>
<p class="MsoNormal"><span style="font-size:11.0pt">Cambridge, MA 02139</span><o:p></o:p></p>
<p class="MsoNormal"><span style="font-size:11.0pt">p: 617.253.7239</span><o:p></o:p></p>
<p class="MsoNormal"><span style="font-size:11.0pt">e: <a href="mailto:cbrooks@mit.edu">cbrooks@mit.edu</a></span><o:p></o:p></p>
<p class="MsoNormal"> <o:p></o:p></p>
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