Enzymes offer advantages over chemical catalysts.Geometrical (sterical) and physical (bonding) complementarityEnzymes lower the activation energy often by induced fit (and substrate strain!)Structural DynamicsDynamics through long-range coupled molecular motions: Example DHFRExample: THE RIBOSOMECHEM 451 1st Edition Lecture 3Outline of Last Lecture I. Darwinian Chemistry, Continueda. Briggs-Rauscher Oscillating Chemical ReactionII. Symmetry breakingIII. Levinthal’s paradoxIV. FractalsV. Hypercycles and Metabolisma. Self vs. non-selfVI. EndosymbiosisOutline of Current Lecture II. Enzymes vs. chemical catalystsIII. Geometrical (sterical) and physical (bonding) complementaritya. Role of waterIV. Induced fit and substrate strainV. Structural Dynamicsa. Example 1: DHFRb. Example 2: The ribosomeCurrent LectureEnzymes offer advantages over chemical catalysts.- Higher Reaction rates (106 to 1012-fold acceleration)- Milder reaction conditions (<100 0C, in water, near neutral pH)- Greater reaction specificity (e.g., the ribosome)o High-fidelity (very little error)- Can be regulated (allostery, covalent modification, product inhibition, gene expression regulation)o Allostery: ligand binds remotely from active site, inducing conformational changes within the enzyme, possibly enhancing or inhibiting the reactiono Covalent modification (e.g., phosphorylation, lysine methylation or acetylation, side-chain interactionso Product inhibition: Le Chatelier’s Principle pushes back the reaction to equilibriumThese notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.o Gene expression regulation: certain genes can be either more or less expressed, leading to either more or less product made in the cell, and this can be changed dynamically in minimal time- Can evolve to become more efficient- All enzymes work together for the survival of the organism.Geometrical (sterical) and physical (bonding) complementarity- Enzymes have a complex 3-dimensional fold with a binding pocket on the surface.- Examples of interactions that give rise to very tight, very specific bindingo Hydrophilic/hydrophobic interactionso Hydrogen bondso Ion-ion interactions (positive-negative interactions)o Stericso Van Der Waals- Role of water: water surrounds the substrate in solution!o Hydrogen bonds between water and substrateo Water molecules fill the enzyme pocket – when substrate binds with enzyme, water must be displacedo Consequently, removing water molecules costs energy, which must be made up by the energy gained when the substrate binds to the pocket Counterbalance between loss of energy in removing water AS WELL AS restriction of substrate-enzyme complex’s motiono Water is an unusual molecule – has a higher density in liquid form than in solido High dielectric constant – strong dipole moment, stronger than protein’s dielectric constant.o Favorable, but not irreversibleEnzymes lower the activation energy often by induced fit (and substrate strain!)- Enzymes DO NOT change the thermodynamics! (ΔG remains the same)o Accelerate reaction by lowering transition state energy, even if they change the interaction of substrate and producto Allows more molecules to cross activation energy barrier- Stabilize transition state MORE than reactant or product – bind the transition state tightly!o Transition state is chemically different than substrate or producto Enzymes fit transition state better than reactant or producto Ex.) Acid-base catalysis: you cannot lower the pH too much due to optimal enzyme pH Alternatively, place specific acids and bases in areas where they will have specific interactions for the transition state- Induced-fit: enzyme molds around the substrate- Substrate strain: substate changes shape to adopt to pocket- Both molding mechanisms allow for specific placement; MORE molding leads to stabilization of transition state- Enzymes are perfect for structural dynamics!Structural Dynamics Structural Dynamics - A multitude of different conformations that interconvert rapidly on the timescale of the reaction- Dynamics determine the rate of the reaction- Rate constant is a probability of overcoming transition energy state.Dynamics through long-range coupled molecular motions: Example DHFRDyhydrofolate Reductase (DHFR): activates dyhydrofolate to become tetrahydrofolate (reduction reaction)- NADPH transfers a hydride ion to carbon, reducing a double bond- Important in metabolism and methylating lysine in covalent modifications- DHFR is good for fighting cancer.o Active enzyme in a cancer cell that divides rapidly – requires a lot of metabolic turnover, activation of methyl groups for methylation reactionso Also used for enzymologyo 2 Substrates: NADPH (cofactor) and dihydrofolateo In active site of enzyme, the two substrates come close together Two carbons (NADPH and dihydrofolate planar ring) transfer a hydrideo Coupled molecular motions: Ex.) Aspartate-122 hydrogen-bonded to glycine, phenylalanine interactingelsewhereIf you mutate the aspartate, then you lose the activityThe hydrogen bond is important for the entire group of interactions that ultimately couple the entire range of enzyme with NADPH cofactor that “push” the cofactor closer to substrateEnzyme as a whole has “breathing motions” – network of H-bonds form in a network of side chains that ALL push together to bring the substrate and cofactor close enough together so that hydride can be transferred between the two.Couplet in motion of longer-scale and local-scale interactionsExample: THE RIBOSOMEThe ribosome: a “big” example for long-range molecular motions- Complex reaction siteo small subunit binds mRNA, uses initiation factors assembling into the initiation complex o forms complex with large subunit (some initiation factors dissociate); ribosome isnow activeo Elongation: tRNAs come in, bringing in each amino acid, peptidyl transferases create peptide bonds Factor comes in to help create bond, then translocate tRNA along small subunit to create peptide bond along back end of large subunito Each cycle, a new tRNA brings in another amino acid (can be performed up to 60 times per second)o Release factor cleaves off polypeptide chain, and two subunits fall apart, mRNA isliberatedo 3 binding sites: A, P, E- Certain cofactors are needed – “neck