Ligand configurational entropy and protein binding Chia-en A. Chang, Wei Chen, and Michael K. Gilson...
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Transcript of Ligand configurational entropy and protein binding Chia-en A. Chang, Wei Chen, and Michael K. Gilson...
Ligand configurational entropy and protein
bindingChia-en A. Chang, Wei Chen, and Michael K. Gilson – PNAS(2007)
Presented by Christopher Williams
Remember K*?
Uses conformational entropy of side chains to better predict redesign mutations
What about ligands?
Entropy is lost on binding How much? What kind? Do we care?
Configurational Entropy
Configurational Entropy
Conformational Entropy Vibrational Entropy
Configurational Entropy
Conformational Entropy Vibrational Entropy
Configurational Entropy
Conformational Entropy Vibrational Entropy
Rotation/ Translation
Torsion
Angle Bending
Bond Stretching
Energy Well
More Wells
Wider Well
Higher Conform
ational Entro
py
Higher Vibrational Entropy
How to measure entropy
S = k ln(W)k = Boltzman constantW = Multiplicity
j
The test case
Amprenavir, an HIV protease inhibitor
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
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
Configurational Entropy
Conformational Entropy Vibrational Entropy
Rotation/ Translation
Torsion
Angle Bending
Bond StretchingThere is correlation among the “separate” components of configurational entropy
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
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
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
Applications to design
Optimizing drugsEntropy loss inhibits bindingRigid ligands have less entropy to lose
Applications to design
Improving Scoring FunctionsCurrent functions overweight conformational
entropy, underweight vibrationalVaries by ligand
Applications to design
Computational savingsVibrational entropy dominatesMay not have to enumerate every minumum
Chia-en A. Chang, Wei Chen, & Michael K. Gilson. Ligand configurational entropy and protein binding. 2007 PNAS 104(5):1534-1539
Questions
Mining Minima
Margin of Error: ± 0.8 kcal/mol
q.e.d