Lecture 4. Thursday, September 7. Principles of Protein Structure.

Lecture 4. Thursday, September 7. Principles of Protein Structure.

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Unformatted text preview: Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 1 John Kuriyan: University of California, Berkeley Lecture 4. Fall 2006. 1 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 2 The relatively small barriers to rotations about single bonds (unless bulky substituents are present) means that molecules alter conformation readily at room temperature. When double bonds, or partial double bonds, are present, rotations are hindered: The polypeptide chain contains two torsion angles that can rotate easily (Φ & Ψ) and one that is fixed in either trans or cis (ω). The allowed values of Φ and Ψ are restricted to values for which the peptide chain does not collide with itself. 2 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 3 Linus Pauling: Famous 20th century chemist who worked out structures of the amino acids and proposed the structures of α helix and β sheet. Pauling proposed the following resonance structures. 3 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 4 The “Ramachandran Diagram” is a map of the Van der Waals energy of a peptide containing only two alanine residues, as a function of the backbone torsion angles Φ and Ψ. For polyalanine, these two torsion angles completely define the conformation of the molecule. When a Ramachandran diagram is calculated using only Van der Waals (VDW) energy, it shows which conformations of the peptide avoid inter-atomic collisions. It does not say whether or not these conformations would be suitable for hydrogen bond formation. 4 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 5 The remarkable property of protein chains is that those conformations which are favored by the Ramachandran diagram are also optimal for hydrogen bonding. α-helices and β-strands are predicted to be favorable by the Ramachandran diagram, and they also optimize internal hydrogen bonding. 5 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 6 6 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 7 β-strands can form parallel and anti-parallel interactions: This is schematically drawn as: β-strands also form anti-parallel interactions: This is schematically drawn as: Whether helices or strands are formed by particular segments of the protein chain are controlled by the R groups (sidechains). Sidechain conformations are also restricted by collisions (steric). 7 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 8 Collision between sidechains can rule out certain conformations of the chain: Sidechain - sidechain interactions can stabilize sheets or helices: α-helices and β-sheets in folded proteins are usually amphipathic: 8 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 9 In an amphipathic helix, residues on one side of the helix are polar, and those on the other side are nonpolar: Likewise, β-sheets can also be amphipathic: 9 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 10 Amphipathic helices can pack against each other to form stable structures: 10 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 11 The hydrophobic effect is the dominant force in driving protein folding. What then is the role of hydrogen bonding? When the protein folds, residues in the hydrophobic core lose hydrogen bonds with water. By requiring the formation of α helices and β sheets the hydrogen bonds impose a defined structure on the peptide chain. But they may contribute little or no net stability to the folded protein. 11 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 12 Stability o f p acking w ill d epend o n s hape complementarily at the interface sequence of the helices determines if they will pack together. α-helices actually have a slight natural curvature, so pairs of interacting helices often form a long structure called the “coiled – coil”: In a coiled coil the number or residues per turn is 3 ⋅5 (instead of 3⋅6 in a regular α helix), so residues are on the same face every 7 residues. 12 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 13 This is the actual sequence of a very simple protein motif called a leucine zipper. This gives rise to an (i, i+3) and (i, i+4) pattern. Amphipathic β-sheets can pack against each other, or against amphipathic α-helices: One common pattern is to have alternating helices and strands interacting with each other: 13 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 14 Electrostatic interactions can dictate the specificity of strand-strand pairings: “CAP” residues can start and end helices 14 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 15 In these sorts of ways, the sequence of the chain determines the structure of the protein. Protein folds are made by combining such units of super-secondary structure: These basic kinds of interactions are combined in many different ways to generate a wide assortment of proteins. It is not possible to list all the possible kinds of protein architectures, but we can look at some of the general principles. 15 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 16 There are 3 major classes of protein folds: (1) all α (2) α+β (3) all β all α proteins The simplest type of all α protein is called a 4-helix bundle: 16 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 17 Trying to align the i, i+4 ridge lines on two α helices gives a helix packing angle of ~50°. 17 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 18 α/β Structures Parallel β strands are often connected by helices. α / β barrel structures are formed by closing the βstrands in a ring (usually 8 stranded): This s tructure i s v ery c ommon, p articularly i n metabolic enzymes. Active site is usually in mouth of barrel. 18 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 19 Active sites of proteins are usually located at crevices or clefts in the structure. In chemical reactions, reactants need to be excluded from water. In binding events, substrates need to be enfolded by the protein. In non-barrel (open) β structures, active sites are often located at directional “switch points” in the chain: Membrane Proteins So far our discussion has centered on soluble or globular proteins. Characteristics of these proteins: 19 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 20 With each domain the secondary structural elements are small: 20 Restricted: For students enrolled in CHEM 130/MCB 100A, UC Berkeley, Fall 2006 ONLY Page 21 Structure of a typical lipid: There are different kinds of membrane proteins: 21 Protein torsion angles John Kuriyan UC Berkley Chem130-MCB-100A, Fall 2006 Lecture 4 To run the animations, you will need to use the PYMOL demos that can be downloaded from the course web page Backbone torsion angles Rotation of the ψ torsion angle dotted yellow lines represent COLLISIONS Rotation of the φ torsion angle dotted yellow lines represent COLLISIONS Ramachandran Diag ram an α helix this α helix is amphipathic: one face is hydrophobic, one face is hydrophilic a β sheet this β sheet also has hydrophobic and hydrophilic faces sidechain torsion angles are also restricted by collisions probability of finding different amino acids in helices, sheets and turns ...
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