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SUMMARY:Free Energy methods to study complex biological phenomena - Dr Fra
 ncesco Gervasio\, Spanish National Cancer Research Centre\, Madrid
DTSTART:20100505T131500Z
DTEND:20100505T141500Z
UID:TALK24163@talks.cam.ac.uk
CONTACT:Susan Harding
DESCRIPTION:Protein plasticity represents both a challenge and an opportun
 ity for\ncomputational drug design. Exploring the conformational space of 
 a\ntarget with sufficient detail is computationally very demanding and\nof
 ten beyond the reach even for state-of-the-art atomistic molecular\nsimula
 tions techniques. If it were possible\, however\, it could open\nthe avenu
 e to the design of more selective drug candidates. Here we\nshow how metho
 ds developed to accelerate rare events can be used to\nstudy large-scale c
 onformational transitions\, protein folding and\nligand binding.\n\nUsing 
 a new sampling method which is able to find the low free energy\nchannel 
 between an initial and final state [1] we determined the\natomistic dynam
 ics of the open-to-closed movement of the cyclin\ndependent kinase 5 (CDK5
 ). We found that the inactivation movement has\na two-step mechanism in wh
 ich  Arg149 plays a key role\, allowing a\nconcerted movement of the C-ter
 minal and N-terminal lobes.  A\ncomplementary method\, Metadynamics [2] wa
 s used to study the mode of\ninhibition of a COX-2 selective drug [3] and 
 the folding mechanism of\nHIV-1 protease monomer.\n\n1. D. Branduardi\, F.
  L. Gervasio and M. Parrinello. Rare events in\nmolecular systems: From A 
 to B in Free Energy Space J. Chem. Phys.\,\n2007\,126\, 054103\,\n\n2. A. 
 Laio and F. L. Gervasio* Metadynamics: a method to simulate rare\nevents a
 nd reconstruct the free energy in biophysics\, chemistry and\nmaterial sci
 ence Rep. Prog. Phys. \, 2008\, 71\, 126601 (22p).\n\n3. V. Limongelli\, F
 .L. Gervasio et al. Proc. National Acad. Sci. USA\,\n2010\,  107\, 5411–
 5416.\n
LOCATION:Unilever Lecture Theatre\, Unilever Centre\, Department of Chemis
 try
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