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JBB2026 Fall 2012 Lectures 2 & 3 -- Gil Privé Protein Structure • Peptide

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JBB2026 Fall 2012 Lectures 2 & 3 -- Gil Privé Protein Structure • peptide conformations and residue preferences • elements of secondary structure • supersecondary structure and motifs • packing of helices and sheets • chain topologies • internal packing • protein interfaces • membrane proteins • multimeric proteins • domain motions 1 The Machinery of Life David S. Goodsell http://mgl.scripps.edu/people/goodsell 2 Tyr Thr Gly Cys Ile Ile Ala Gly 3 φ =180 ; ψ=180 φ =-60 ; ψ=-45 4 Note: unsaturated C-N bond length is 1.45 Å -Peptide bond has ~40% double bond character - dihedral is constrained. Bond lengths Bond angles Dihedrals sp2-hybridized atoms Shorter 120° (flat) More restrained (trans) sp3-hybridized atoms longer 109° (tetrahedral, Less restrained often chiral) (gauche-, gauche+, trans) 5 Crambin TTCCPSIVARSNFNVCRLPGTPEAICATYTGCIIIPGATCPGDYAN 1CRN 6 partial charges in peptide produces dipoles These are additive and can produce a macroscopic dipole (esp. in α-helices). Figure from Branden and Tooze Intro to Protein Structure 7 One way of categorizing the 20 amino acids - each amino acid has particular characteristics 8 Amino acid hydrophobicity Relevant amino acid properties Size (number of atoms) Shape (torsion angles) Flexibility (how many degrees of freedom?) Charge (N , O ; pKa values) Polarity (electronic structure) Hydrophobicity Aromaticity (F, Y) 9 Protein conformations The conformation is the arrangement of the atoms in 3D space. The most stable conformation is at a potential energy minimum Proper treatment is quantum mechanical - but this is intractable with proteins (too many atoms). We use Newtonian mechanics and describe the system as a set of potential energy terms, each with a particular form. The overall potential energy can be broken down into several energy functions: LOCAL bond length (1,2) (strong) bond angle (1,3) (strong) dihedral angle (1,4) (medium) NON-LOCAL solvation / hydrophobic effect van der Waals (packing, steric clashes) electrostatics (incl. hydrogen bonds) conformational entropy These are additive- calculate the overall potential energy as the sum of these individual functions 10 LOCAL bond length (1,2) bond angle (1,3) dihedral angle (1,4) NON-LOCAL van der Waals (packing, steric clashes) electrostatics (incl. hydrogen bonds) hydrophobic effect E = f(bonds, angles, dihedrals, vdW, electrostatics, H) E = f(x,y,z) Can describe the energy of the system from the positions of the atoms! (need to consider the structure of the entire system, including waters) 11 H φ ψ ω φ ψ ω H φ ψ H 12 “Classic” Ramachandran Plot Calculated energy surface Based on hard sphere potentials - simple form of the van der Waals potential. (theoretical) 13 Conformational energy of butane as a function of the central torsion angle Boltzman distribution: Populate according to energies 40 39 38 37 36 potentialenergy (kcal/mol) 35 0 90 180 270 360 e g+ t g- e Torsion angle (°) Population: 0% 15% 70% 15% 0% 14 Potential surfaces for side chain dihedral angles This defines the major rotamers for each amino acid. E.g. χ 1 χ 2 plot for Phenylalanine gauche- χ 2 χ2 χ1 gauche+ φ ψ χ 1 Why can’t Phe χ 2 be trans? gauche- gauche+ trans 15 Ch1 - Chi2 plots 16 φ ψ omega From: Introduction to Protein Structure (Branden and Tooze) 17 Potential energy curve for the peptide omega dihedral angle : Barriers for dihedral angle rotation can be attributed to the electronic structure of the amide bond (delocalized). Energy difference between cis and trans can be attributed to: -the exchange interaction of electrons in adjacent bonds -repulsive interactions between overlapping bond orbitals - steric clashes between atoms (Clash between groups 1 and 4 in the 1,4 bond disfavors cis). Note : only two minima here- why? 18 Xaa-Pro is an exception (peptide bond preceding a proline) - lower barrier to interconversion - only ~2 kcal/mol energy difference between cis and trans omega bond - ~6% of Xaa-Pro have cis omega angles, otherwise v. rare (<0.5%) 19 The only kind of of symmetric three dimensional structure for a linear polymer is a helix Helix: combination of a rotation and a translation (screw) n: residues per turn d: rise per residue (Å) (other parameters include pitch, twist, …) In this example, n = 8 d 20 n: residues per turn d: rise per residue Cantor and Schimmel Biophysical Chemistry 21 Snake toy Features: • Fixed bond lengths and angles • 8-fold torsional potential minima at φ = 0, 45, 90, 135, 180, 225, 270, 315, 360° • Linear polymer of 11 units 811 = 8.6 X 109 conformers! (not all are accessible) • Torsion dihedral is not colinear with the chain This makes it interesting… the toy would be pretty boring otherwise. But note that the angles are not the same as in a peptide 22 Twist/step 0° 45° 90° 180° 23 Name Frequency* φ (°) ψ (°) n d (Å) H-bonding 310 helix ~4% -74 -4 +3.0 2.0 i,i+3 α helix ~35% -57 -47 +3.6 1.5 i,i+4 αL helix - +57 +47 -3.6 1.5 i,i+4 Π helix - -57 -70 +4.3 1.1 i,i+5 Collagen (PP type II) Fibres -78 +149 -3.3 2.9 planar β-sheet (para) - -115 +115 2.0 3.2 twisted β- sheet parallel ~25% -120 +135 -2.3 3.3 interstrand twisted β- sheet antiparallel ~8 -139 +135 -2.3 3.3 interstrand B-DNA - - 10 3.4 interchain *Crude estimate in globular proteins 24 β α 25 Three rules for secondary structure 1) Local “bonded” potentials must be minimized - bond lengths (1,2) - bond angles (1,3) - dihedrals (1,4) (Ramachandran) regular: all (phi,psi) the same 2) Satisfy main chain hydrogen bonding - Typically, >90% of the potential backbone hydrogen bond donors and acceptors are involved in hydrogen bonds 3) No unfavourable steric interactions - Ramachandran 26 Observed (φ,ψ) distributions from over 500 high quality experimental structures (97,368 residues) From: Lovell et al. Proteins 50, 437 (2003). 27 General and special cases 28 ψ φ ψ φ any residue preceding Proline Proline Pre-Pro - φ is relatively normal Proline - φ “fixed” at -60° ψ is restricted to 90 - 180° ψ = -55° or 145° 29 Residue-specific Ramachandran plots 30 C Alpha helix Hydrogen bond between carbonyl of residue i with amide-H of residue i + 4 i i+1 i+2 i+3 i+4 i+5 i+6 i+7 N 31 i,i+3 i,i+4 i,i+5 n: residues per turn 3 α π 10 R d: rise per residue n,d: 3.0, 2.0Å 3.6, 1.5Å 4.3, 1.1Å 32 33 Long helices - rarely straight. smooth bends (e.g. tropomyosin - coiled coiled dimers) kinks waters often bridge i,i+4 H-bond. membrane proteins often amphipapthic - one face interacting with bulk solvent, one with protein core. lots of strains due to longer-range contacts the proteins (non-local effects). Transmembrane helices 60 Å radius of curvature: bending is not energetically expensive (< 2 kcal/mol for a 5-turn helix) 34 Saposin A kink in alpha3 closed form open form (ligand bound) (apo) 35 Y54 (n) 36 Beta-sheets Parallel Antiparallel 37 Parallel beta sheet 38 Antiparallel beta sheet 39 • Parallel sheets •generally buried •Less twisted •Antiparallel and mixed sheets •Generally, one side exposed •Can withstand greater distortions (twisting and beta-bulges) 40 A beta-bulge leads to higher twisting in a sheet 41 There are ~8 types of turns residue number i i+1 i+2 i+3 turn type Iʼ (60, 30) (90, 0) IIʼ (60,-120) (-80, 0) These definitions are approximate (+/- 30°) 42 Intrinsically disordered proteins (aka natively unfolded proteins, intrinsically unstructured, ...) - no stable secondary or tertiary structure under physiological conditions - dynamic - abundant in eukaryotes, less in bacteria and archaea - highly abundant in certain classes of protein (e.g. signaling proteins) - often involved in protein-protein interactions (disorder-order transitions) - often have lower sequence complexity - typically rich in polar residues and disorder-promoting residues (R, K, E, Q, S, P, G) - typically depleted of hydrophobic and aromatic residues (I, L, V, W, Y, F) - structure ensembles not equivalent to chemically denatured proteins that are natively folded 43 Natively unfolded proteins have low overall hydrophobicity and large net charge. CH plot for ordered proteins (open circles) and natively unfolded proteins (grey). Uversky et al. Proteins 41, 415 (2000). 44 Chain Topologies (tertiary structure) Huge variety some are regular (e.g. TIM barrel; β-barrel), some are not. Proteins often assembled from “domains” “Never” see knots Minimum size for stability ~60 amino acids if small - often stabilized by disulfides, co-factors, etc e.g. Zinc fingers If extracellular, often have - S-S bonds. - glycosylation Salt bridges are not very common 45 Internal Packing of a folded protein • Inside of a protein is packed as tightly as in an organic crystal - largely driven by the hydrophobic effect and van der Waals packing (also electrostatics, etc.) • position of the side chain - the path of the main chain determines the Calpha-Cbeta vector • side chain rotamers - coordinated - entropy effects - dihedral angles of the side chains are critical! • Can think of a packed protein interior as a “3D jigsaw puzzle” • small cavities can occur 46 Shape and Dynamics in self-assembled systems - detergent micelles vs. well-packed proteins Amphiphiles are driven to self association by the hydrophobic effect. But the chains can't all point in since this would not produce a uniform packing density in the micelle (water is excluded, and nature abhors a vacuum). There is not one satisfactory packing arrangement. The micelle structure is highly dependent on the shape and size of the monomers. The fast dynamics are due to the fact that no one packing arrangement is favored over another.
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