2. PROTEINS

3. PROTEINS

5. Levels of Protein Structure

6. Primary structure = order of amino acids in the protein chain

7. Charged and polar R-groups tend to map to protein surfaces

8. Non-polar R-groups tend to be buried in the cores of proteins Myoglobin Blue = non-polar R-group Red = Heme

9. Amino Acids Are Joined By Peptide Bonds In Peptides -  -carboxyl of one amino acid is joined to  -amino of a second amino acid (with removal of water) - only  -carboxyl and  -amino groups are used, not R-group carboxyl or amino groups

10. Chemistry of peptide bond formation

11. The peptide bond is planar This resonance restricts the number of conformations in proteins -- main chain rotations are restricted to  and 

12. Primary sequence reveals important clues about a protein small hydrophobic large hydrophobic polar positive charge negative charge Evolution conserves amino acids that are important to protein structure and function across species. Sequence comparison of multiple “homologs” of a particular protein reveals highly conserved regions that are important for function. Clusters of conserved residues are called “motifs” -- motifs carry out a particular function or form a particular structure that is important for the conserved protein. motif

13. Secondary structure = local folding of residues into regular patterns

14. The  -helix In the  -helix, the carbonyl oxygen of residue “i” forms a hydrogen bond with the amide of residue “i+4”. Although each hydrogen bond is relatively weak in isolation, the sum of the hydrogen bonds in a helix makes it quite stable. The propensity of a peptide for forming an  -helix also depends on its sequence.

15. The  -sheet In a  -sheet, carbonyl oxygens and amides form hydrogen bonds. These secondary structures can be either antiparallel (as shown) or parallel and need not be planar (as shown) but can be twisted. The propensity of a peptide for forming  -sheet also depends on its sequence.

16. Why do Secondary Structures form

17. Tertiary structure = global folding of a protein chain

18. Tertiary structures are quite varied

19. Quaternary structure = Higher-order assembly of proteins

20. Examples of other quaternary structures Tetramer Hexamer Filament SSBDNA helicase Recombinase Allows coordinated Allows coordinated DNA binding Allows complete DNA binding and ATP hydrolysis coverage of an extended molecule

21. Quaternary Structures

22. Classes of proteins Functional definition: Enzymes: Accelerate biochemical reactions Structural:Form biological structures Transport:Carry biochemically important substances Defense:Protect the body from foreign invaders Structural definition: Globular:Complex folds, irregularly shaped tertiary structures Fibrous:Extended, simple folds -- generally structural proteins Cellular localization definition: Membrane:In direct physical contact with a membrane; generally water insoluble. Soluble:Water soluble; can be anywhere in the cell.

23. Protein Overview

25. from sequence to structure Function to dynamics Need to understand physical principles underlie the passage

30. LEVINTHAL PARADOX 100 a.a in general If there are 10 states/a.a 10 100 conformations

33. Three Folding Problems Computational:Computational: Protein structure prediction from an amino acid sequence..Folding speed: “Levinthal paradox” the kinetic question how can a protein fold so fasts The folding code:The folding code: The ”thermodynamic” question of how a native structure results from interatomic forces acting on an amino acid sequence

34. What if proteins misfold? Diseases such as Alzheimer's disease, cystic fibrosis, BSE (Mad Cow disease), and even many cancers are believed to result from protein misfolding. When proteins misfold, they can clump together ("aggregate"). These clumps can often gather in the brain, where they are believed to cause the symptoms of Mad Cow or Alzheimer's disease.

35. Experimental Structure Prediction Electron Microscopy: Structural information for large macromolecules at low resolution NMR (Nuclear Magnetic Resonance) Spectroscopy: A solution of protein is placed in a magnetic field and the effects of different radio frequencies on the resonance of different atoms in proteins. X-ray crystallography: The beam of x-rays are passed through a crystal of protein. Atoms in the protein crystal scatter the x-rays, which produce a diffraction pattern on a photographic film.

36. Pros and Cons None of them is high throughput technology NMR –Size of protein limited (about 200 residues) –Protein must be soluble –can provide the structure in near physiological condition –can provide informations about dynamics X-ray Crystallography –Must be able to crystallize protein –Accurate

37. X-ray crystallography

38. NMR

40. Why Predict Protein Structures? High Resolution Structures better than 3Å To eliminate protein structure determination To speed up drug discovery

41. Sequence --------------> Structure Function ‘Protein folding problem’ Bioinformatics. Sequence alignments A fundamental paradigm of protein science: The amino acid sequence encodes the structure; the structure determines the function Modelling and simulations Dill & Chan From a computational point of view:

45. What is a molecular dynamics simulation? Simulation that shows how the atoms in the system move with time Typically on the nanosecond timescale Atoms are treated like hard balls, and their motions are described by Newton’s laws.

48. Molecular Dynamics Theory

49. MD as a tool for minimization Energy position Energy minimization stops at local minima Molecular dynamics uses thermal energy to explore the energy surface State A State B

50. Folding Energy Landscape

51. The Folding @ Home initiative (Vijay Pande, Stanford University) http://folding.stanford.edu/

52. The Folding @ Home initiative