identifying hidden free energy barriers
DESCRIPTION
Identifying Hidden Free Energy Barriers. Chris Neale , Angel García , Régis Pomès. Rensselaer Polytechnic Institute. Creative Commons (Mariana Ruiz). Creative Commons ( Asd.and.Rizzo ). Vertex Pharmaceuticals, Boston 2014 Workshop on Free Energy Methods in Drug Design. x34,000. - PowerPoint PPT PresentationTRANSCRIPT
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Identifying Hidden Free Energy BarriersChris Neale, Angel García, Régis Pomès
Vertex Pharmaceuticals, Boston2014 Workshop on Free Energy Methods in Drug Design
Creative Commons (Asd.and.Rizzo) M.W. Brightman , T.S. Reese,J. Cell. Biol. 1969. 40(3):648-77
x34,000
Creative Commons (Mariana Ruiz)
Rensselaer Polytechnic Institute
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Ord
er p
aram
eter
G.M. Torrie, J.P. Valleau, J. Comput. Phys., 1977, 23(2):187-199
Umbrella sampling
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1. Problems• Sampling convergence• Force field accuracy
2. Progress• Systematic sampling errors
Outline
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C. Neale, J.C.Y. Hsu, C.M. Yip, R. Pomès, Biophys. J., 2014, 106(8):L29-L31
Indolicidin-bilayer binding
100nm
T. Beveridge, J. Bacteriol., 1999, 181(16):4725-4733
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Why do these simulations
take so long to converge?
• Peptide conformational change• Bilayer reorganization
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arginine
C. Neale, W.F.D. Bennett, D.P. Tieleman, R. Pomès, J. Chem. Theory Comput., 2011, 7(12):4175-4188.
Bilayer reorganization
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waterBilayercenter
Immersion depth autocorrelationarginine
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Hidden free energy barriersFree energy contour map
a
a b
b
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Replica exchange enhances convergence
C. Neale, C. Madill, S. Rauscher, R. Pomès, J. Chem. Theory Comput., 2013, 9(8):3686-3703.
arginine
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The random walk contains information about hidden barriers
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arginine
Replica mobility
water
Bilayer(upper leaflet)
Bilayer(lower leaflet)
water
One line for each replica
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incident transmitted
reflected
The transmission factor, T, as a measure of local replica diffusion
00
0
T ii
I i
zT z
z
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water
Bilayercenter
C. Neale, C. Madill, S. Rauscher, R. Pomès, J. Chem. Theory Comput., 2013, 9(8):3686-3703
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correlates with ratioT ACF
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predictsratioT ACF
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Testing the prediction:10 x 5-μs restrained simulations
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Summary
• Long convergence times related to bilayer reorganization
• Replica exchange of umbrellas enhances convergence
• The transmission factor identifies regions of the order parameter that are prone to systematic sampling errors
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Supervisors: Collaborators:
Drew Bennett Jenny Hsu Chris MadillLoan Huynh
Sarah Rauscher Tom Rodinger Peter Tieleman Chris Yip
Angel García
Régis Pomès