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Lecture 20. Thursday, November 9. Introduction to Allostery.

# Lecture 20. Thursday, November 9. Introduction to...

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Restricted: For students enrolled in Chem130/MCB100A, UC Berkeley, Fall 2006 ONLY 1 John Kuriyan: University of California, Berkeley Chem C130/MCB 100A, Fall 2006, Lecture 20 Review of Dissociation Constants/Association Constants In the last lecture we considered the equilibrium between a ligand, L, and its target, P (e.g., a protein). The equilibrium constant for the binding reaction is: K A = [ PL ] [ P ][ L ] association constant The equilibrium constant for the dissociation reaction is: K D = [ P ][ L ] [ PL ] dissociation constant and a D K K 1 = The standard free energy change upon binding is given by: G ° = -Rt ln K A G ° = + Rt ln K D

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Restricted: For students enrolled in Chem130/MCB100A, UC Berkeley, Fall 2006 ONLY 2 It is useful to plot ƒ, the fractional occupancy, in terms of D K L ] [ , i.e., the concentration of ligand in terms of the dissociation constant. f = [ L D 1 + [ L D When we consider the ligand concentration [ L ] in terms of its proportion to K D , we can estimate how much drug we have to add to saturate the target. The ligand concentration range that is within a factor of 10 on either side of the dissociation is the range in which the receptor switches from being completely unbound to completely bound. We can see this effect by plotting the ligand concentration of a logarithmic scale. f
Restricted: For students enrolled in Chem130/MCB100A, UC Berkeley, Fall 2006 ONLY 3 Note: the y-axis of the graph is ƒ, the fractional occupancy. Thus, by the time the ligand concentration is ~10 K D , the target, or receptor, is essentially completely bound. Consider ATP, which have low to medium affinity for many proteins (K D ~10 -5 – 10 -6 M); K D for ATP can be as low as millimolar for the protein, and ATP forms many hydrogen bonds with the protein. Organic compounds (drugs) which have high affinity for protein targets (K D ~10 -9 M or lower) often form very few hydrogen bonds with the protein. ATP makes 5-6 hydrogen bonds to the protein, several involving the charged phosphate groups. This would seem to contradict the information given previously, particularly since some of the hydrogen bonds formed between ATP and the protein involve charged

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Restricted: For students enrolled in Chem130/MCB100A, UC Berkeley, Fall 2006 ONLY 4 groups, which are stronger. We would expect H ° -100 kJ and K D 10 -18 !
Restricted: For students enrolled in Chem130/MCB100A, UC Berkeley, Fall 2006 ONLY 5 Since both free ATP and the protein form hydrogen bonds with water, the net free energy change involves a balance of interactions. In effect, the “strength” of hydrogen bonds is reduced considerably in water. The net free energy change for forming a hydrogen bond in water is reduced to: G

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Lecture 20. Thursday, November 9. Introduction to...

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