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No lecture Wed Apr 6 so students can participate in the Student-Faculty Conference

No lecture Wed Apr 6 so students can participate in the Student-Faculty Conference. We encourage you to attend the SFC on Wed. 4/6 starting at 11am in Ramo Auditorium. Please check the full SFC schedule at http://www.ugcs.caltech.edu/~arc/ PJB will still have office hours at 2pm on Wednesday.

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No lecture Wed Apr 6 so students can participate in the Student-Faculty Conference

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  1. No lecture Wed Apr 6 so students can participate in the Student-Faculty Conference We encourage you to attend the SFC on Wed. 4/6 starting at 11am in Ramo Auditorium.Please check the full SFC schedule at http://www.ugcs.caltech.edu/~arc/ PJB will still have office hours at 2pm on Wednesday.

  2. An experimental method to determine macromolecular structures: X-ray Crystallography Crystal Growth Electron Density Protein Model X-ray Data

  3. Love hides in molecular structures.Jim Morrison, Love Hides, from Absolutely Live, The Doors Macromolecular structure Sugars are energy sources for cells. Macromolecules are created by covalently linking small molecules (monomers or subunits) into long chains or polymers. Proteins catalyze reactions and perform MANY other functions in cells. Nucleic acids (DNA, RNA) store and transmit hereditary information. Little Alberts, Figure 2-27

  4. Transcription Translation Nucleic acid structure DNA ----------> RNA --------------> Protein The information for the amino acid sequence of each protein is stored in DNA as a code. DNA is transcribed into RNA, which serves as a “messenger” that is translated into protein.

  5. Clicker question What is the significance of the structure of DNA? 1) It explains how genetic material is copied. 2) It explains how proteins are translated. 3) It explains how mutations occur. 4) It can be made into beautiful works of art.

  6. Clicker question Which part of the DNA structure explains how DNA is replicated? 1) The sugar-phosphate backbone 2) The deoxynucleotides 3) The amino acids 4) The basepairs

  7. Clicker question Which part of the DNA structure explains how DNA is replicated? The sugar-phosphate backbone The deoxynucleotides The amino acids The basepairs “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.” (J. Watson & F. Crick, 1953, Nature 171: 737-738)

  8. DNA is made from four nucleotide building blocks: Adenine (A), Thymine (T), Cytosine (C), Guanine (G) Little Alberts, Figure 2-25

  9. DNA structure video

  10. Watson and Crick deduced the structure of DNA from this diffraction image What is the significance of the “X”? Find out at this website: http://www.pbs.org/wgbh/nova/photo51/ Find out more about Rosalind Franklin, the scientist who recorded this diffraction pattern, in this article: "Rosalind Franklin and the Double Helix," by Lynne Osman Elkin, Physics Today, March 2003 http://www.physicstoday.org/vol-56/iss-3/p42.html

  11. The structure of DNA explains how genetic information is copied • Each strand of the DNA double helix is complementary to its partner strand, so each can act as a template for synthesis of a new complementary strand (“semi-conservative” replication). • Base-pairing allows a simple way for cells to pass on their genes to descendents.

  12. Incorrect DNA model Even Linus Pauling, a brilliant chemist who discovered a-helices and b-sheets in proteins, wasn’t infallible. But (important point here) he was thinking and proposing solutions to important problems.

  13. Triplet code

  14. The Genetic Code-- it’s (pretty much) universal 64 triplets encode 20 amino acids (most amino acids are encoded by more than one triplet) plus a termination signal (3 different stop codons).

  15. What about the structure of RNA?

  16. Single stranded RNA can fold into complicated 3D shapes resulting from intramolecular basepairing 07_05_RNA.jpg Structure of a ribozyme, an RNA enzyme Hairpin structures result from regions of sequence that are complementary to each other (inverted repeats).

  17. What do proteins do? • Catalysis -- enhancement of reaction rates (e.g., a polymerase makes polymers from monomers) • Transport and storage (e.g., hemoglobin) • Immune protection (e.g., antibodies) • Control of gene expression (e.g., repressors) • Mechanical support (e.g., collagen in skin and bone)

  18. What is an enzyme? Enzymes are proteins* that catalyze (accelerate) chemical reactions. Many of their names end in “ase” (e.g., polymerase, kinase, protease). Substrate: molecule at the beginning of the reaction.Product: molecule at the end of the reaction. The activity of an enzyme is determined by its 3-D structure. Enzymes lower the activation energy for a reaction. *Some RNA molecules can act as enzymes to catalyze reactions, but most enzymes are proteins.

  19. Proteins we will discuss in Bi 1 DNA-binding proteins Enzymes, including DNA and RNA polymerase, ribosomes* HIV proteins Antibodies and immune system proteins Cytoskeletal proteins (actin, tubulin) Almost every time we discuss a function that is carried out in a cell or a virus, it is done by a PROTEIN. *Ribosomes contain proteins, but their catalytic activies are carried out by RNA

  20. Proteins are made from amino acids linked together by planar peptide bonds

  21. Clicker question: Peptide bonds are planar because the N-C’ bond has partial double bond character. Linus Pauling (Caltech) provided evidence for this when he was able to show that… 1) A trans conformation is favored for the N-C’ dihedral angle for most amino acids. 2) The distance measured for a peptide bond was shorter than expected for a typical C-N single bond. N-C’ bonds break spontaneously in aqueous solvents. Hemoglobin contains many double bonds.

  22. 1.33Å C Clicker question: Peptide bonds are planar because the N-C’ bond has partial double bond character. Linus Pauling (Caltech) provided evidence for this when he was able to show that… 1) A trans conformation is favored for the N-C’ dihedral angle for most amino acids. The distance measured for a peptide bond was shorter than expected for a typical C-N single bond. N-C’ bonds break spontaneously in aqueous solvents. 1.45Å C N

  23. Properties of the 20 amino acids in proteins See also http://www.imb-jena.de/IMAGE_AA.html and p. 74-75 of Essential Cell Biology

  24. Figure 3-9 Proteins are held together by noncovalent interactions

  25. Glu Arg Clicker question: the type of interaction most likely to occur between a glutamic acid residue and an arginine residue is… 1) Electrostatic 2) H-bond 3) VdW 4) Hydrophobic

  26. Glu Arg Clicker question: the type of interaction most likely to occur between a glutamic acid residue and an arginine residue is… 1) Electrostatic 2) H-bond 3) VdW 4) Hydrophobic

  27. PROTEIN STRUCTURE Primary structure: sequence (G S H S M R Y F Y T S . . .) Secondary structure: a-helix, b-sheet Tertiary structure:How the secondary structural elements are arranged to form a compact structure.

  28. a-helix

  29. a-helix

  30. Antiparallel b-sheets Parallel

  31. b-sheet

  32. Color conventions for amino acids www.cryst.bbk.ac.uk/PPS95/ course/3_geometry/peptide1.html See pages B8-B9 at end of your textbook

  33. Different ways to depict a protein structure Ball & stick of featured area Wire diagram Ribbon diagram Blue: positive Red: negative Surface representation (GRASP image) Space filling:van der Waals Petsko G.A., Ringe, D., Protein Structure and Function 2004, figure 5-5, pg. 173.

  34. Primary Structure: Amino Acid Sequence Enter Somethign

  35. Model of HIV protease http://mgl.scripps.edu/projects/tangible_models/movies

  36. Tertiary Structure: An Example of an All-Alpha Protein, Hemoglobin Subunit Rotated 90 Degrees

  37. Tertiary Structure: An Example of an All-Beta Protein, Flu Virus Neuraminidase 1) Rotate 90 Degrees

  38. Tertiary Structure: An Example of an Alpha/Beta Protein, Triose Phosphate Isomerase 1) Rotate 90 Degrees

  39. Tertiary Structure: An Example of an Alpha + Beta Protein, TATA Binding Protein 1) Rotate 90 Degrees

  40. From Tertiary to Quaternary Structure: Hemoglobin as an Example Quaternary structure -- the relative arrangement of two or more individual polypeptide chains Protein assemblies can contain one type of polypeptide (homo-oligomer) or multiple types (hetero-oligomer) Example: Hemoglobin (oxygen carrier in blood) Hemoglobin is a hetero-tetramer composed of two alpha subunits and two beta subunits

  41. Hemoglobin, Tertiary Structure

  42. Hemoglobin, Quaternary Structure Tetrameric Hemoglobin Single Subunit

  43. Clicker question: A good design for a stable folded protein is… 1) A polar/charged core with mostly nonpolar residues on the surface. • A nonpolar core with mostly polar/charged residues on the surface. 3) An even mix of polar/charged and nonpolar residues in the core and on the surface. 4) Fatty acids on the inside, ribonucleotides on the outside. 5) Ralph Lauren.

  44. Clicker question: A good design for a stable folded protein is… A) A polar/charged core with mostly nonpolar residues on the surface. B) A nonpolar core with mostly polar/charged residues on the surface. • An even mix of polar/charged and nonpolar residues in the core and on the surface. • Fatty acids on the inside, ribonucleotides on the outside. • Ralph Lauren.

  45. The Protein Folding Problem: the sequence of a protein cannot (yet) be used to predict its 3D structure ?

  46. Protein Structure Prediction “Critical Assessment of techniques for Structure Prediction” (CASP 9) -- a competitionFor more information or to enter, see http://predictioncenter.org/ Winners earn an automatic “A+” in Bi 1 (retroactively, if necessary)

  47. Foldit • New Nature Video - Foldit: Biology for gamers - August 04, 2010http://blogs.nature.com/news/thegreatbeyond/2010/08/new_nature_video_foldit_biolog.html • From David Baker’s webpage: (http://depts.washington.edu/bakerpg/drupal/)Foldit is a revolutionary new computer game enabling you to contribute to important scientific research. Join this free online game and help us predict the folds of unsolved proteins as well as designing new proteins to cure diseases. We’re collecting data to find out if humans' pattern-recognition and puzzle-solving abilities make them more efficient than existing computer programs at pattern-folding tasks. If this turns out to be true, we can then teach human strategies to computers and fold proteins better than ever!

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