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PROTEIN PHYSICS
LECTURE 18
Protein Structures:Thermodynamic Aspects (2)
• Why protein denaturation is an “all-or-none” phase transition, unlike the globule-coil transition in “normal” polymers?
• “Energy gap” and “all-or-none” melting. “Protein-like” heteropolymers.
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Globule-to-coil transition in “normal” synthetic polymers: It is not of the “all-or-none” type
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Globule-to-coil transition in “normal” synthetic polymers is not of an “all-or-none” type.
Besides, globule-to-coil transition in polymers resembles evaporation rather than melting or sublimation, while protein denaturation resembles melting or sublimation of a crystal rather than evaporation of a liquid.
Why?Special construction of protein chain.
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Why protein denaturation is an “all-or-none” phase transition?
Peculiarities of protein structure: - Unique fold; - Close packing;- Flexible side chains at rigid backbone
- Side chains rotamers
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Free energy barrier # between Native and Denatured states
#
C ⇐OIL
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Free energy barrier # between Native and Denatured states
Start of the sidechain liberation
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TransitionsNative → GlobuleNative → Coilhave to overcome the barrier # :therefore,
“all-or-none”
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(Uversky, … Ptitsyn, 1992)
Unfolding of MG
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(Tanford, 1968)
?
“PRE-MOLTEN”
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“All-or-none” melting: a result of the “energy gap”
Start of the sidechain liberation
~ ln[M(E)]
←[small M(E)]
IS THE GAP “NATURAL”?
____
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Random Energy Model (REM)M ~ 2N structures of N various particles
interactions in “ i”: ~ N
Energy of “structure i”: Ei = Σ ελ(i) ⇒ Statistics: <E>, σλ
P(E) ~exp[-(E - <E>)2/2σ2]
Probabilitythat given structurehas E:
For all M structures:
RARE
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“Energy gap” and “all-or-none” melting. “Protein-like” heteropolymers.
REM:
REM
REM(random energy model)
ENERGY SPECTRA
GAP WIDTH ΔE
The gap has some (small) chance to be be of a significant width
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WHY DO PROTEINS USUALLY HAVE ONLY 1 NATIVE FOLD?
REM:
1 NATIVE FOLD: WONDER, ~exp(-ΔE/kTC) ;2 NATIVE FOLDS: WONDER SQUARED…
(but: serpins)
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GAP WIDTH ΔE:MAIN PROBLEM OF EXPERIMENTAL PROTEIN PHYSICSPHYSICAL ESTIMATE: ???
BIOLOGICAL ESTIMATE:1 0F ~1 000 000 000 RANDOM SEQUENCES MAKES A “PROTEIN-LIKE” STRUCTURE (SOLID, WITH A SPECIFIC BINDING: PHAGE DISPLAY).
THIS IMPLIES THAT ΔE ~ 20 kTC(WHILE ΔHmelt ~ 100 kTM >> ΔE):
consistent withNARROW GAP, i.e.,
TM IS ONLY A LITTLE HIGHER THAN TC.
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Protein Structures: Thermodynamics
• Protein denaturation: cooperative and, moreover, an “all-or-none” transitionin small proteins and separate domains.
• Solid native state, unfolded coil & “molten globule”.
• Why protein denaturation is an “all-or-none” phase transition, unlike the globule-coil transition in “normal” polymers?
• “Energy gap” and “all-or-none” melting. “Protein-like” heteropolymers.
?
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Comparing globule-to-coil transition in polymersto 1-st order phase transition like evaporation
Separate monomers Polymer chain
T2 >T1
Per a particle:ΔF = ΔH - T ΔS= μ (chemical
potential)Transition: ΔF1= ΔF2
stable statesunstable states
T2 > T1