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A Hitch-Hiker’s Guide to Molecular Thermodynamics What really makes proteins fold and ligands bind Alan Cooper Amsterdam: November 2002 Chemistry Department Joseph Black Building, Glasgow University Glasgow G12 8QQ, Scotland
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“Concepts and tools for medicinal chemists” + What makes this protein fold, and what controls its stability ?
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“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 ?
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“ 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
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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 …
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Thermodynamic Equilibrium, expressed in terms of the Gibbs Free Energy change, reflects just the balance between these opposing tendencies… G = H - T S 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
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Both enthalpy and entropy are integral functions of heat capacity... ….from which G = H - T. S So C p is the key - if we can understand heat capacity effects, then we can understand everything else.
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Calorimetric techniques... Differential scanning calorimetry (DSC) Isothermal titration calorimetry (ITC) Pressure perturbation calorimetry (PPC)
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So, what is the role of water? So C p is the key - if we can understand heat capacity effects, then we can understand everything else. And C p 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!
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G= H-T S G=-RTln(K) Δ G must negative for a reaction to take place. Δ G = 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 Δ G is 0; but lets pretend…) If we make G=18.6 for [A] (again, this is nonsence because we cannot know G, only Δ G) (so, G is 1.38 bigger for [A] which means better for [B]) then [B] becomes 10 times bigger than [A].
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G= H-T S 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.
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G= H-T S Good for Δ S: Entropy of water. Bad for Δ S: Entropy of protein.
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