ligand configurational entropy and protein binding chia-en a. chang, wei chen, and michael k. gilson...
TRANSCRIPT
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Ligand configurational entropy and protein
bindingChia-en A. Chang, Wei Chen, and Michael K. Gilson – PNAS(2007)
Presented by Christopher Williams
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Remember K*?
Uses conformational entropy of side chains to better predict redesign mutations
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What about ligands?
Entropy is lost on binding How much? What kind? Do we care?
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Configurational Entropy
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Configurational Entropy
Conformational Entropy Vibrational Entropy
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Configurational Entropy
Conformational Entropy Vibrational Entropy
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Configurational Entropy
Conformational Entropy Vibrational Entropy
Rotation/ Translation
Torsion
Angle Bending
Bond Stretching
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Energy Well
More Wells
Wider Well
Higher Conform
ational Entro
py
Higher Vibrational Entropy
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How to measure entropy
S = k ln(W)k = Boltzman constantW = Multiplicity
j
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The test case
Amprenavir, an HIV protease inhibitor
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Results
Configurational entropy loss on binding: 26.4 kcal/mol
# of accessible conformations in solution: 960 # of accessible conformations bound: 1
ΔS = RT ln(960)
Conformational entropy contribution: 4.1 kcal/mol
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Results
Configuational entropy loss on binding: 26.4 kcal/mol
Entropy loss: torsion only: 12.2 kcal/mol Entropy loss: rotation/translation only: 15.7
kcal/mol
12.2 + 15.7 = 27.9 != 26.7 kcal/mol
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Configurational Entropy
Conformational Entropy Vibrational Entropy
Rotation/ Translation
Torsion
Angle Bending
Bond StretchingThere is correlation among the “separate” components of configurational entropy
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Proof?
Similar results were returned by a separate analysis“Quasiharmonic analysis” – essentially an MD
approachCompare 11.6 kcal/ mol to 12.3 kcal/mol
Cannot test in wetlebCannot yet measure separate components of
entropy
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Predictions and Observations
Configurational entropy has a similar magnitude effect to electrostatics or hydrophobics ~25 kcal/molDoes not include proteinVaries by ligandVaries by tightness of binding
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Predictions and Observations
Vibrational entropy loss dominatesNot conformational/rotamer lossThis challenges conventional thinking
Certain atom centers are more prone to vibrational entropysp3 versus ring structures
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Applications to design
Optimizing drugsEntropy loss inhibits bindingRigid ligands have less entropy to lose
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Applications to design
Improving Scoring FunctionsCurrent functions overweight conformational
entropy, underweight vibrationalVaries by ligand
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Applications to design
Computational savingsVibrational entropy dominatesMay not have to enumerate every minumum
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Chia-en A. Chang, Wei Chen, & Michael K. Gilson. Ligand configurational entropy and protein binding. 2007 PNAS 104(5):1534-1539
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Questions
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Mining Minima
Margin of Error: ± 0.8 kcal/mol
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q.e.d