SignalingLectureFinal

Cooperativity and binding interestingly many if not

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Cooperativity and binding Interestingly, many (if not most) of the real world binding problems we care about in biology do not satisfy the simple binding model (sometimes called the Langmuir adsorption isotherm) we have worked out so far. The classic example (i.e. the hydrogen atom of binding problems) is hemoglobin.
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Hemoglobin as a case study in cooperativity several 100s hemoglobin molecules Oxygen binds to heme on the hemoglobin molecules Hemoglobin - the classic example of ligand-receptor binding Cooperativity: the binding energy for a given ligand depends upon the # of ligands that are already bound to the receptor Intuitively: conformational change upon binding => the next ligand experiences a different binding energy apps.uwhealth.org The heme group includes a porphyrin ring (gray line) + iron The protein hemoglobin: 4 polypeptide chains (2 α -chains, 2 β - chains), each carries a heme group => protein can bind up to 4 molecules of O 2
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The nature of the Hill function
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Hemoglobin as a case study in cooperativity Hemoglobin-oxygen binding: language of two-states occupation variables. State of system is described with the vector where σ i : i = 0 (unbound), i = 1 (bound) Q.: what is the average # of bound O 2 molecules as a function of the O 2 concentration (or partial pressure)? A toy model of a dimoglobin To illustrate the idea of cooperativity: imagine a fictitious dimoglobin [=dimeric hemoglobin] molecule which has 2 O 2 binding sites ( e.g., clams ) => 4 distinct states The energy of the system: Energy associated with O 2 being bound to one of the 2 sites measure of the cooperativity
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A toy model of a dimoglobin The grand partition function (sum over the 4 states): => compute the probabilities for each classes of states: unoccupied, single occupancy, double occupancy Single occupancy Both sites occupied Parameters used: Δε =–5 k B T, J= –2.5 k B T, c 0 = 760 mmHg
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Talking across the membrane Membrane proteins are characterized in some cases by transmembrane alpha helices and cytosolic domain that passes along the signal.
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Coupling receptors to enzyme action Receptor binding changes the probability of the “active” state.
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Cooperativity and binding Interestingly many if not most of...

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