1. CS790 – BioinformaticsProtein Structure and Function1 Review of fundamental concepts  Know how electron orbitals and subshells are filled Know why atoms “prefer” a specific number of covalent bonds: O2N3H1 C4S2  O and N tend to form hydrogen bonds, C does not. Symmetry and electronegativity

2. CS790 – BioinformaticsProtein Structure and Function2 Fundamental concepts, cont’d  Types of molecular interactions Covalent  polar  ionic Hydrogen bonds Van der Waals interactions  Concentraction: moles/liter  Acids and bases pH =  log[H + ] pH = pKa : protonated/unprotonated species at equilibrium pH < pKa : more protonated pH > pKa : less protonated

3. CS790 – Bioinformatics The Structure and Functions of Proteins CS 790 – Bioinformatics

4. Protein Structure and Function4 Proteins are chains of amino acids  Polymer – a molecule composed of repeating units

5. CS790 – BioinformaticsProtein Structure and Function5 Amino acid composition  Basic Amino Acid Structure: The side chain, R, varies for each of the 20 amino acids CR CC H N O OH H H Amino group Carboxyl group Side chain

6. CS790 – BioinformaticsProtein Structure and Function6 The Peptide Bond  Dehydration synthesis  Repeating backbone: N–C  –C –N–C  –C Convention – start at amino terminus and proceed to carboxy terminus OO

7. CS790 – BioinformaticsProtein Structure and Function7 Peptidyl polymers  A few amino acids in a chain are called a polypeptide. A protein is usually composed of 50 to 400+ amino acids.  Since part of the amino acid is lost during dehydration synthesis, we call the units of a protein amino acid residues. carbonyl carbon amide nitrogen

8. CS790 – BioinformaticsProtein Structure and Function8 Side chain properties  Recall that the electronegativity of carbon is at about the middle of the scale for light elements Carbon does not make hydrogen bonds with water easily – hydrophobic O and N are generally more likely than C to h-bond to water – hydrophilic  We group the amino acids into three general groups: Hydrophobic Charged (positive/basic & negative/acidic) Polar

9. CS790 – BioinformaticsProtein Structure and Function9 The Hydrophobic Amino Acids Proline severely limits allowable conformations!

10. CS790 – BioinformaticsProtein Structure and Function10 The Charged Amino Acids

11. CS790 – BioinformaticsProtein Structure and Function11 The Polar Amino Acids

12. CS790 – BioinformaticsProtein Structure and Function12 More Polar Amino Acids And then there’s…

13. CS790 – BioinformaticsProtein Structure and Function13 Planarity of the peptide bond Phi (  ) – the angle of rotation about the N-C  bond. Psi (  ) – the angle of rotation about the C  -C bond. The planar bond angles and bond lengths are fixed.

14. CS790 – BioinformaticsProtein Structure and Function14 Phi and psi  =  = 180° is extended conformation  : C  to N–H  : C=O to C  CC C=O N–H

15. CS790 – BioinformaticsProtein Structure and Function15 The Ramachandran Plot  G. N. Ramachandran – first calculations of sterically allowed regions of phi and psi  Note the structural importance of glycine Observed (non-glycine) Observed (glycine) Calculated

16. CS790 – BioinformaticsProtein Structure and Function16 Primary & Secondary Structure  Primary structure  Primary structure = the linear sequence of amino acids comprising a protein: AGVGTVPMTAYGNDIQYYGQVT…  Secondary structure Regular patterns of hydrogen bonding in proteins result in two patterns that emerge in nearly every protein structure known: the  -helix and the  -sheet secondary structureThe location of direction of these periodic, repeating structures is known as the secondary structure of the protein

17. CS790 – BioinformaticsProtein Structure and Function17 The alpha helix      60°

18. CS790 – BioinformaticsProtein Structure and Function18 Properties of the alpha helix      60°  Hydrogen bonds  Hydrogen bonds between C=O of residue n, and NH of residue n+4  3.6 residues/turn  1.5 Å/residue rise  100°/residue turn

19. CS790 – BioinformaticsProtein Structure and Function19 Properties of  -helices  4 – 40+ residues in length  Often amphipathic or “dual-natured” Half hydrophobic and half hydrophilic Mostly when surface-exposed  If we examine many  -helices, we find trends… Helix formers: Ala, Glu, Leu, Met Helix breakers: Pro, Gly, Tyr, Ser

20. CS790 – BioinformaticsProtein Structure and Function20 The beta strand (& sheet)    135°   +135°

21. CS790 – BioinformaticsProtein Structure and Function21 Properties of beta sheets  Formed of stretches of 5-10 residues in extended conformation  Pleated – each C  a bit above or below the previous  Parallel/aniparallel  Parallel/aniparallel, contiguous/non-contiguous

22. CS790 – BioinformaticsProtein Structure and Function22 Parallel and anti-parallel  -sheets  Anti-parallel is slightly energetically favored Anti-parallelParallel

23. CS790 – BioinformaticsProtein Structure and Function23 Turns and Loops  Secondary structure elements are connected by regions of turns and loops  Turns – short regions of non- , non-  conformation  Loops – larger stretches with no secondary structure. Often disordered. “Random coil” Sequences vary much more than secondary structure regions

24. Levels of Protein Structure  Secondary structure elements combine to form tertiary structure  Quaternary structure occurs in multienzyme complexes Many proteins are active only as homodimers, homotetramers, etc.

25. CS790 – BioinformaticsProtein Structure and Function25 Protein Structure Examples

26. CS790 – BioinformaticsProtein Structure and Function26 Views of a protein WireframeBall and stick

27. CS790 – BioinformaticsProtein Structure and Function27 Views of a protein SpacefillCartoonCPK colors Carbon = green, black, or grey Nitrogen = blue Oxygen = red Sulfur = yellow Hydrogen = white