a hitch-hiker’s guide to molecular thermodynamics what really makes proteins fold and ligands bind
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A Hitch-Hiker’s Guide to Molecular Thermodynamics What really makes proteins fold and ligands bind. Alan Cooper. Chemistry Department Joseph Black Building, Glasgow University Glasgow G12 8QQ, Scotland. Amsterdam: November 2002. +. “C oncepts and tools for medicinal chemists”. - PowerPoint PPT PresentationTRANSCRIPT
A Hitch-Hiker’s Guide to Molecular Thermodynamics
What really makes proteins fold and ligands bind
Alan Cooper
Amsterdam: November 2002
Chemistry DepartmentJoseph Black Building, Glasgow UniversityGlasgow G12 8QQ, Scotland
“Concepts and tools for medicinal chemists”
+
What makes this protein fold, and what controls its
stability ?
“Concepts and tools for medicinal chemists”
+
What makes this protein fold, and what controls its
stability ?
What are the thermodynamic forces responsible for ligand binding ? Can we use them to
design better ligands ?
“ Concepts and tools for medicinal chemists”
Microcalorimetry: analytical uses for
biomolecular interactions and
stability
Thermodynamic homeostasis,
compensation; hydrogen-bonded
lattices…
...the role of water in biomolecular
interactions
There is a natural tendency for all things (even atoms & molecules) to roll downhill - to fall to lower energy.
H wants to be negative
This is opposed (at the molecular level) by the equally natural tendency for thermal/Brownian motion (otherwise known as “entropy”) to make things go the other way…
…and this effect gets bigger as the temperature increases.
T.S wants to be positive
A bluffer’s guide to Thermodynamic Equilibrium…
Thermodynamic Equilibrium, expressed in terms of the Gibbs Free Energy change, reflects just the balance between these opposing tendencies…
G = H - TS
Equilibrium is reached when these two forces just balance (G = 0).
The standard free energy change, G, is just another way of expressing the equilibrium constant, or affinity (K) for any process, on a logarithmic scale…
G = -RTlnK
H(T) = H(Tref) + Tref
T
Cp .dT
S(T) = S(Tref) + Tref
T
(Cp /T).dT
Both enthalpy and entropy are integral functions of heat capacity...
….from which G = H - T.S
So Cp is the key - if we can understand heat capacity effects, then we can understand everything else.
Calorimetric techniques...
• Differential scanning calorimetry (DSC)
• Isothermal titration calorimetry (ITC)
• Pressure perturbation calorimetry (PPC)
So, what is the role of water?
So Cp is the key - if we can understand heat capacity effects, then we can understand everything else. And Cp is largely determined by the interactions between water and the macromolecule(s).
In figure b many more waters are free than in a. And free waters are happy waters!
G=H-TS G=-RTln(K)
Δ G must negative for a reaction to take place. ΔG = 1.38 kCal/Mole means a factor 10 difference in an equilibrium.
Example:A <==> B [A] = [B] G=17.2 for [A] and for [B], so
we have a 50/50 equilibrium (it is impossible to know that G=17.2, we can only know that ΔG is 0; but lets pretend…)
If we make G=18.6 for [A] (again, this is nonsence because we
cannot know G, only ΔG) (so, G is 1.38 bigger for [A] which means better for [B]) then [B] becomes 10 times bigger than [A].
G=H-TS
Good for Δ H: 1) Contacts in protein (H-bonds, Van der Waals
interactions, salt bridges, aromatic stacking, etc).2) H-bonds between water molecules
Bad for Δ H: 1) H-bonds between water and part of protein that gets
buried.
G=H-TS
Good for Δ S: Entropy of water.
Bad for Δ S: Entropy of protein.