HC1

• For enzyme catalysis the proximity and orientation are critical. This enhances the chance of the reaction and the usefullness of the outcome of the reaction. The structure of an enzyme is not rigid but flexible and put molecules in close proximity of each other. To shield from the bulk a microevironment is created.
• The reaction rate is enhanced by substrate distortion, which is when the substrate changes shape to fit the active site. This stabilizes the transition state.
• The better the enzyme is at binding the transition state, the faster the reaction will be.
• You need to know the pka of the sidechains

  
• The amino acid side chains are often involved in catalysis, in particular in Bronsted acid-base catalysis. Some amino acid side chains can serve as ligands for metals.
• A perfect catalyst means that is has the highest rate that is fundamentally atainable.
• Ligand can serve to modulate the properties, like acidity and accessibility, and to bring the molecules closer.
• The chemistry for enzymes happens mostly at the active site. The active site comprises 10-20% of the total volume of the enzymes. A hydrophilic cleft or cavity containing is an array of amino acid side chains that can bind the substrate.
• High substrate selectivity is typical of enzume catalysis, this is achieved by highly specific non-covalent interactions. These interactions are H-bonds, ionic bonds and VdW interactions.
• Amino acids are involved in the catalysis and substrate binding.
• A hydrophobic compound in a hydrophobic pocket maximizes inter-water hydrogen bonding. The removal of a hydrophobic compound, allows an energy gain in the water you leave behind as the hydrogen bonding can be more optimal.

  
• Hydrogen bonds have two roles in interactions, they position and they activate.
• Many enzymes bind one or more metal ions at the active site. The most common ones are Mg, Zn, Fe, Cu, Mn, Co, Mo.
• A metal at the active site can either have a structural or a catalytic role. The catalytic role is often as a Lewis acid or rexox agent.
• Nature uses first row transition metals, manmade more 2nd and 3rd row. The first row is radical chemistry and is harder to control as it is more radical chemistry
• Enzymes can offer multiple interactions at the same time. The multiple interactions allows for aligning substrates and doing acid/base chemistry in the same active site. The enzymes need to be big to do this.
• Noncompetitive inhibition is when the substrate binds on a different site but still shuts down the enzyme
• Competitive inhibition is when a different molecule binds instead of the substrate so it shuts down the enzyme
• What is noncompetitive inhibition?

  The substrate binds on a different site but still shuts down the enzyme
• Selective binding does not lead to high catalytic activity
• Koshland's induced fit is

  1. Precise orientation of catalytic groups is required for enzyme action
  2. The substrate causes an appreciable change in the 3D relationship of the amino acids at the active site (binding of the substrate leads to a reconformation of the enzyme)
  3. Only a substrate will bring about the necessary changes in the protein structure and lead to proper alignment; a non-substrate will not
• The rate of accelaration can be given by  kcat/kuncat =e(Euncat-Ecat)/RT. A typical ratio is in the order of 10^6-10^14
• The reduction in Ea is called the transition state stabilization
• The enzyme-substrate complex makes reactions intramolecular, this is called the proximity and orientation effect.
• Proximity and orientation effects lower the entropic barrier to forming the transition state because they pre-organize the substrates so that they lose less entropy during the formation of the transition state than the free substrates would
• Effective concentration is the concentration of the participating group that one would need in the intermolecular reaction to get the same rate as in the intramolecular one
• The proximity and orientation effects can be quantified using the effective concentration of the reactants in the reaction
• Why does the rate drop?

  Because there is too much free rotation so too few effective collisions. The structure is too rigid. The base can not be in the position to activate water in its own molecule

  A) a

  
• • Enzymes should not bind substrates too tightly, but rather selectively bind the transition state for optimal catalysis
• Strong TS binding is good.

  Strong S binding lowers the well before the TS (b)

  
• You want a substrate to bind, but not to bind too strongly. A volcano plot shows that there is an optimum. If they bind too strong or too weak it will be a bottlenek. If the heat of adsorption is too weak the rate will be not be high because there is hardly any substrate on the surface. If the heat of adsorption is too strong it will be too high because it sits happily on the surface.
• What is shown here and what should be on the axis?

  A volcano plot

  A) Reaction rate

  B) Heat of adsorption

  
• What is the role of the Zn ion and of His4?

  Zn2+ is a lewis acid and will activate the H2O for nucleophilic attack on CO2. The coordination of water polarizes the O-H, making it more acidic. His4 acts as a base to gradually deprotonate the coordinated H2O, as a result the OH nucleophile is created to attack CO2.

  
• Enzymes are dynamic structures that undergo conformational changes