1. Overview of Biomolecules proteinsLipid membraneDNA

2. Proteins: A chain of linked subunits These subunits are amino acids (also called protein residues for historical reasons). There are 20 different amino acids with different physical and chemical properties. The interaction of these properties allows a chain of the amino acids (upto 1000’s long) to fold into a unique, reproducible 3D shape.

3. Amino acid structures Fig. 5.3

5. Representations of proteins 1-d sequence: Alanine-Tyrosine-Valine= ALA-TYR-VAL= A-Y-V

6. Representations of proteins: 2-d THH HHHHHTLLLH HHHHHGGGLS STTEEEEEEE

7. Representations of proteins: 3-d

8. Protein features Protein can be stabilized by salt bridges Protein can be folded to a unique structure due to the existence of disulfide bonds Protein may function as an enzyme whose active sites are crucial for its function

9. A simple model of a cell proteinsLipid membraneDNA

10. DNA structures DNA packs in the nucleus to form chromosome

11. DNA structure

12. DNA is a sequence too It has a common back bone, and side chains, though only 4 kinds. A sequence of these subunits is also specified as a string: ACTTAGGACATTTTAG, which is a simplified representation of a chemical structure.

13. DNA is a sequence too DNA uses an alphabet of 4 letters (ATCG), i.e. bases. Long sequences of these 4 letters are linked together to create genes and control information.

14. Information in DNA DNA encodes proteins: each amino acid can be specified by 3 bases. Ribosome reads a DNA sequence and creates the corresponding protein chain. GENETIC CODE: 64 mappings of 3 bases to 1 amino acid.

15. Genetic code

16. The gene for myoglobin ctgcagataa ctaactaaag gagaacaaca acaatggttc tgtctgaagg tgaatggcag ctggttctgc atgtttgggc taaagttgaa gctgacgtcg ctggtcatgg tcaggacatc ttgattcgac tgttcaaatc tcatccggaa actctggaaa aattcgatcg tttcaaacat ctgaaaactg aagctgaaat gaaagcttct gaagatctga aaaaacatgg tgttaccgtg ttaactgccc taggtgctat ccttaagaaa aaagggcatc atgaagctga gctcaaaccg cttgcgcaat cgcatgctac taaacataag atcccgatca aatacctgga attcatctct gaagcgatca tccatgttct gcattctaga catccaggta acttcggtgc tgacgctcag ggtgctatga acaaagctct cgagctgttc cgtaaagata tcgctgctaa ctgggttacc agggttaatg aggtacc BASE COUNT 155 a 108 c 115 g 129 t MVLSEGEWQLVLHVWAKVEADVAGHGQDILIRLFKSHPETLEKFDRFKHLKTEAEM KASEDLKKHGVTVLTALGAILKKKGHHEAELKPLAQSHATKHKIPIKYLEFISEAI IHVLHSRHPGNFGADAQGAMNKALELFRKDIAAKYKELGYQG

18. Genes and control The set of all genes required for an organism is the organism’s GENOME. Human genome has 3,000,000,000 bases divided into 23 linear segments (chromosomes). A gene has on average 1340 DNA bases, thus specifying a protein of about 447 amino acids. Humans have about 35,000 genes = 40,000,000 DNA bases = 3% of total DNA in genome. Humans have another 2,960,000,000 bases for control information. (e.g. when, where, how long, etc...)

19. Genotype and phenotype Genotype—the genetic sequences associated with an individual organism. Phenotype—the observable non-sequence features of an individual organism (e.g. color, shape, activity of an enzyme)

20. How do we proceed? In order to obtain insight into the ways in which genes and gene products function: Analyze DNA and protein sequences to search clues for structure, function and control – sequence analysis Analyze structures to search clues for sequences, function and control – structural analysis Understand how sequences and structures leads to functions – functional analysis

21. But what are functions of genes? Signal transduction: sensing a physical signal and turning into a chemical signal Structural support: creating the shape and of a cell or set of cells Enzymatic catalysis: accelerating chemical reactions otherwise too slow to be useful for living things Transport: getting things in and out of a compartment.

22. But what are functions of genes? Movement: contracting in order to pull things together or push things apart Transcription control: deciding when other genes should be turned on/off Trafficking: affecting where different elements end up inside a cell.

23. Evolution is the key Common descent of organisms implies that they will share many basic approaches Development of new phenotypes in response to environmental pressure can lead to specialized approaches More recent divergence implies more shared approaches between species The important thing is which is shared and which is not unshared. This is also important for drug discovery in biomedicine.

24. Seeing is Believing: Biomolecular Structures and Computer Graphics

25. Levels of Structure in Proteins (hemoglobin as an example)

26. I.Levels of Structure in Proteins A.Primary structure = amino acid sequence. B.Secondary structure Definition: Localized regions of the protein that form a “regular” structure; a repeating pattern of bond angles in the polypeptide backbone. Most common structures:  -helix and  -strand C.Tertiary structure The overall 3-D structure of a polypeptide. Includes regions of secondary structure, turns, and regions with seemingly random structure. D.Quarternary structure The 3-D arrangement of protein subunits.

27. The 3-D structure of the polypeptide backbone is completely defined by the  and  angles. Partial double bond character of the peptide bond makes it planar II.Secondary Structure

28. non-planar …..….…...Backbone………...…..planar close (aa1>aa5)..…..H-bonding neighbors……...distant  -helix  -sheet Both involve H-bonding between a backbone carbonyl oxygen and a backbone -NH group. Side-chains are not involved. C=O …. H–N

29.  -helix  -sheet

30. III. Tertiary Structure A.Fibrous proteins twisted  -helices (keratin – hair, skin, nails) super  -sheets (silk) B.Globular proteins Most contain multiple regions of  - and  - structures. Some are predominantly one or the other. Hydrophilic side chains tend to reside on the surface; aliphatic/hydrophobic side-chains tend to be buried inside. Domain: compact, locally folded region of 3-D structure with a specific function.

32. IV.Quaternary Structure A. Only relevant to multi-subunit proteins; refers to relative arrangement of the subunits. B.Subunits can be identical or not. - Hemoglobin has 2  and 2  subunits C.Several types of symmetry exist with regard to the arrangement of subunits. D.Subunits are held together by non-covalent forces: H-bonds, ionic, hydrophobic

33. V.Driving Forces in Protein Folding  G =  H-T  S [  G < 0 means favorable] 1.H (folding)- non-covalent interactions - H-bonds, charge-charge, etc. - breaking old ( H 2 O ) and making new (internal and among H 2 O ) 2.S (folding)- conformational restrictions - folded vs random coil - usually disfavors folding

34. 3. The hydrophobic effect Moving hydrophobic (aliphatic) side-chains from a water-rich to a water-free (hydrophobic) environment  H component is favorable (more H-bonds among water molecules; some van der Waals attraction between hydrophobic side-chains.)  S component is also favorable; loss of water clathrates around hydrophobic side-chains.

35. favorableunfavorable =  H-T  S Contributions to the Free Energy of Folding

36. Representations of Molecular Structure: Bonds Only

38. Representations of Molecular Structure: Atoms Only

39. Representations of Molecular Structure: Atoms and Bonds

40. Representations of Molecular Structure: Ribbons

41. Representations of Molecular Structure: Mixed

42. Representations of Molecular Structure: van der Waals Surface

43. Representations of Molecular Structure: Wire-frame Surface

44. Representations of Molecular Structure: Solvent Excluded Surface

45. Je-2147/HIV Protease Complex

46. HIV Integrase

47. The Small Ribosome Subunit

48. The Large Ribosome Subunit