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Basics of Protein Structure  15 Principles of protein structure Biophysical Chemistry 1, Fall 2010 Fundamentals of protein structure Basics of molecular mechanics and dynamics Reading assignment: Chaps 1 & 2, Appendices A, B, D & E b541_Chapter-01.qxd 11/20/2008 10:54 AM Page 4 FA 4 A Textbook of Structural Biology found. Eukaryotic cells are usually at least 10 times larger than prokaryotic cells and more complex. In eukaryotic cells, the basic prokaryotic cell structure with the plasma membrane and cytoplasm is upgraded with compartments, also called organelles. In the cytoplasm, additional distinctive structures can be found. In some cases their interior is segregated from each other by a membrane. The most common organelles are: (i) the nucleus storing the cell genetic material and where replication and gene expression takes place; (ii) the cytosol, where protein syn- thesis and many essential biochemical reactions take place; (iii) the mitochon- drion, a power plant and energy storage compartment; (iv) the endoplasmatic reticulum and Golgi apparatus, where proteins are packaged and sent to further locations; (v) the lysosomes or vacuoles, where polymeric macromolecules, such as proteins, are degraded into usable monomers (Fig. 1.3). It is believed that all organisms on Earth originate from a single kind of uni- cellular organism. Today many millions of different kinds of organisms that do not interbreed with one another can be found and we call them species. They are Cell biology:all successfully not adapted yet to biochemistry! their different environments and in this sense, perfect. However, some of them may not be perfect tomorrow and can thereby become FIGURE 1.3 A schematic picture of an animal cell showing sub-cellular structures, such as nucleus, membrane systems (ER), mitochondrion, etc. (Made by Michael W. Davidson, Florida State University.) b541_Chapter-02.qxd 11/20/2008 10:54 AM Page 15 FA Basics of Protein Structure 15 SUMOylation). The enzymatic or non-enzymatic modifications of amino acid side chains in vivo are further described in App. E. 2.1.2 The Protein Backbone In proteins, the amino acid residues are linked by peptide bonds. The bond between the CO and NH groups has a partial double bond character due to a res- onance between the normal form and a form with a double bond between the C and N. This means that the atoms connecting the two Cα atoms are all in a plane. The ω (omega) torsion angle (Fig. 2.3) for the normal trans peptide bond is close to 180°. Due to steric interactions, the cis peptide bond (ω ≈ 0°) is much less favor- able. For bonds preceding Pro residues, the cis conformation is more common (cis- prolines). This is discussed in Sec. 9.1.1.1. Because of the planarity of the peptide bond, the conformation of the poly- peptide backbone can be described by two torsion angles per residue. These angles, φ and ψ, have restricted values due to steric clashes between the carbonyl oxygen, the hydrogen of the NH group, the hydrogen on the Cα carbon, and the Proteinsside chainare atoms. polymers This was used of to amino define the acids allowed regions as described by the H R H D C D Cα N A C Cα B C ϕ ψ ω B R H A O O R 1.24 H 120.5° 123.5° C Peptide bond Cα ° 1.51 122 1.33 116° 111° N 1.46 Cα ° 119.5° 118.5 1.0 H Peptide R plane H FIGURE 2.3 The peptide bond. The top left figure shows the definition of a torsion angle. The middle figure, where we look along the bond between atoms B and C, shows how we can deter- mine the angles between the bonds AB and CD. The top right drawing shows the names of the torsion angles. In a trans peptide ω ≈ 180°, since the atoms of the peptide bond tends to form a plane (the amide plane). Bottom: The distances and angles between the atoms of a peptide bond. b541_Chapter-02.qxd 11/20/2008 10:54 AM Page 13 FA There are twenty common side chains Basics of Protein Structure 13 Charged Polar Side Chains Amino Acid Side Chains ( at pH 7) – + O CH2 CH2 CH2 CH2 NH3 Lys General Amino Acid CH C NH 2 2 Structure Asp O CH2 CH2 CH2 NH C + – Arg O NH2 R CH2 CH2 C CH2 H + – N H3 NCCOO Glu O N H His Uncharged Polar Side Chains Nonpolar Side Chains –OOC CH2 SH CH2 OH Cys C CH2 Tyr H N Phe Pro CH2 OH Ser OH H CH CH2 CH2 S CH3 H CH3 NH2 CH3 Thr Met Gly Ala CH2 C Asn O NH2 CH3 CH3 CH3 H CH2 CH2 C CH2 CH CH CH Gln O N CH3 CH3 CH2 CH3 Leu Val Ile Trp CH2 FIGURE 2.2 The 20 different side chains of the amino acids. 2.1.1.1 Side chains and their interactions The sequence of amino acid side chains gives the proteins unique properties. They not only determine the fold of the protein, but they also determine surface prop- erties that are important for selective interactions with other molecules and catal- ysis of chemical reactions. Depending on the environment of the amino acids, the pKas given in Table 2.1 can be subject to dramatic changes. For example, if two carboxyl groups are close to each other and no positively charged group balances these negative charges, their pKas may be raised considerably. In addition to arginine, lysine, aspartic acid and glutamic acid, the side chains of cysteine, histidine, serine, threonine and tyrosine can sometimes be charged in physiological environments. The side chains can interact with each other or with the main chain in many different ways (see also App. A). The nonpolar or hydrophobic side chains, mostly The Protein Data Bank (PDB, aka RCSB) http://wwwPDB file.rcsb.org 3e7l Batchelor JD, Doucleff M, Lee CJ, Matsubara K, De Carlo S, Heideker J, Lamers MH, Pelton JG, Wemmer DE. Structure and regulatory mechanism of Aquifex aeolicus NtrC4: variability and evolution in bacterial transcriptional regulation. J Mol Biol (2008) 384(5), 1058-1075. NtrC4: (nitrogen regulatory protein C4) an activator protein that stimulates gene expression by binding sigma-54 sigma-54 (σ54): protein subunit of the RNA polymerase assembly of molecular weight 54 kDa, which is required for the expression of a wide variety of genes Aquifex aeolicus: thermophilic (heat-loving) bacterium “ATOM” cards in a PDB file: PDB file 3e7l ATOM 19 N LEU A 22 13.495 17.685 -7.418 1.00 107.88 N ATOM 20 CA LEU A 22 12.855 16.698 -6.555 1.00 100.06 C ATOM 21 C LEU A 22 11.626 16.031 -7.172 1.00 97.04 C ATOM 22 O LEU A 22 11.508 14.807 -7.158 1.00 94.39 O ATOM 23 CB LEU A 22 12.487 17.336 -5.213 1.00 95.81 C ATOM 24 CG LEU A 22 13.669 17.846 -4.385 1.00 91.39 C ATOM 25 CD1 LEU A 22 13.197 18.737 -3.246 1.00 88.32 C ATOM 26 CD2 LEU A 22 14.492 16.681 -3.861 1.00 88.80 C ATOM ‘card’: ATOM, atom #, atom name, res name, chain ID, res #, x, y, z, occupancy, B-factor, atom type Internal coordinates: bond lengths Inter-atomic distances:(distance between bonded atoms) Atomic coordinates a1 = (a1x, a1y, a1z) a2 = (a2x, a2y, a2z) Bond length 2 2 2 1/2 b12 = ((a2x–a1x ) +(a2y–a1y ) +(a2z–a1z ) ) a2 b12 a1 PDB file 3e7l Bonded distances don’t change much: Bond lengths: Chain A backbone 1.459±0.003 Å 1.527±0.003 Å 1.329±0.001 Å PDB file 3e7l Histogram of backbone distances: Bond length histograms: Chain A backbone CA-C 1.527±0.003 Å C-N 1.329±0.001 Å N-CA 1.459±0.003 Å Bond or “valence”Internal angles: coordinates: valence angles (complement of angle formed by successive chemical bonds) Atomic coordinates a1 = (a1x, a1y, a1z) a2 = (a2x, a2y, a2z) a3 = (a3x, a3y, a3z) Bond vectors b12 = (a2x–a1x, a2y–a1y, a2z–a1z) b23 = (a3x–a2x, a3y–a2y, a3z–a2z) Scalar product b12⋅b23 = (a2x–a1x)(a3x–a2x)+(a2y–a1y)(a3y–a2y)+(a2z–a1z)(a3z–a2z) a2 b23 b12⋅b23 = b12b23 cos(π–θ123) θ123 b12 a3 cosθ123 = –b12⋅b23/(b12b23) a1 cos(π–θ123) = cosπ cosθ123 + sinπ sinθ123 = – cosθ123 Distribution of backbone angles:PDB file 3e7l Valence angles: Chain A backbone 112.0±1.5° 116.4±0.5° 121.7±0.7° Dihedral or torsionInternal angles: coordinates: torsion/dihedral angles (angle between planes containing successive pairs of chemical bonds) Atomic coordinates a1 = (a1x, a1y, a1z) a2 = (a2x, a2y, a2z) a3 = (a3x, a3y, a3z) a3 = (a4x, a4y, a4z) Bond vectors b12=(a2x–a1x, a2y–a1y, a2z–a1z) b23=(a3x–a2x, a3y–a2y, a3z–a2z) b34=(a4x–a3x, a4y–a3y, a4z–a3z) n234 n123 = b12×b23 n234 = b23×b34 n 123 a2 a4 b23 θ234 θ b 123 b34 12 n123·n234 = cosφ1234 a3 (n ×n )·b > 0 => φ > 0 φ1234 123 234 23 1234 (n123×n234)·b23 < 0 => φ1234 < 0 a1 Vector/cross product Vector product or “cross” product: i j k V ! V = v v v 1 2 1x 1y 1z v v v 2x 2y 2z = #v v " v v % i + v v " v v j + #v v " v v % k $ 1y 2z 2y 1z & ( 1z 2x 2z 1x ) $ 1x 2y 2x 1y & ' * = #v v " v v % , v v " v v , #v v " v v % ()$ 1y 2z 2y 1z & ( 1z 2x 2z 1x ) $ 1x 2y 2x 1y & +, c ,c ,c = ( 1 2 3 ) Backbone torsion angles: PDB file 3e7l ∠ CA–C–N–CA Torsion angle vs.
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