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Protein folding
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Protein folding

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  1. Protein folding Process of folding Modeling the process of folding Evolution vs. folding Impact of function on protein evolution

  2. Process Local Interactions Secondary Structure Elements (SSE) Assembly of SSE Equilibrium Structure

  3. Protein folding http://www.blueprint.org/proteinfolding/trades/details/trades_movies.html

  4. Protein folding Important thing to note It is possible that residues that are not doing anything in the folded protein were actually critically important to get the peptide folded in the first place.

  5. Protein folding Simulation studies are demonstrating that the most common protein folds are those who can withstand the most sequence variation over time without affecting their topologies. The prion protein is a posterchild example of the opposite.

  6. Protein Evolution Evolutionary meaning Most common folds are those able to withstand point mutations the best. These are known as designable folds.

  7. Protein folding Marginal stability The most stable folds are not necessarily these with the lowest energy. But these that maximally penalize switching to an alternative conformation.

  8. Protein Evolution Marginal stability Evolutionary implication(s) There is thus selective pressure on residues in protein not only to maintain important interaction, but also to make sure that some interaction NEVER happen.

  9. Summary Proteins fold into energetically stable conformations. For one chain, there are a large number of possible conformations, however. The biological conformation is selected during folding: not necessarily the “best” conformation.

  10. Role of biology on structures A few examples using mapping of rate of evolution. The fitness of a protein is ultimately its biological function, not its structure. We’ll have a look at their structural requirements.

  11. Structural Biology

  12. Outline How genetics encode structure. What make a protein fold. Role of biological function on preserving a fold. Comparing two structures for similarities.

  13. Genetic information and proteins 3D information is encoded into (1D) sequences. ? STKKKPLTQEQLEDARRLKA IYEKKKNELGLSQESVADKM GMGQSGVGALFNGINALNAY NAALLAKILKVSVEEFSPSI AREIYEMYEA Protein structure of CRO repressor in phage Lambda, PDB: 1LMB

  14. Genetic information and proteins The encoding can only be indirect Because there is nothing in the DNA that tells each amino acid where to go.

  15. Genetic information and proteins However, There is a few types of physical interactions that are dominating the process of protein folding.

  16. Components Main Chain Side Chains Side Chains Responsible for the “name”. Can be clustered based on: - chemical properties - Structure This ultimately determine the evolutionary interchangeability. Amino-acids

  17. Protein folding Van der Waal forces The electron clouds around the nuclei are more stable if they can lightly interact with other electron clouds. Makes atoms sticky relative to each other.

  18. Protein folding Electrostatic forces Long range interactions. Pull/Push over longer distances.

  19. Protein folding Hydrogen bonds Electrostatic. Short range, not flexible Can be seen as the velcro holding proteins together.

  20. Protein folding Hydrophobic interactions Water molecules in liquid pack as to minimize their energies This implies that water molecules are more than often are doing H-bond with their neighbors.

  21. Protein folding Hydrophobic interactions If you introduce a droplet of oil in solution, many hydrogen bonds will have to be broken at the interface, at an energy cost. This is why hydrophobic and hydrophilic groups look like they are avoiding each other.

  22. Protein folding During folding, The polypeptide has to follow a strict sequence of event in order to find the correct conformation in a timely fashion.

  23. Protein folding Secondary Structures Stable because of local h-bonds. Makes larger block with fewer freedom of movement

  24. Protein folding Geometry plays a very important role. Because there are only a few angles that can change along the backbone, there is a limited number of ways a protein can fold onto itself.

  25. b al a Secondary structures - Geometry Dihedral Angle Because most main chain atoms are constrained in a “amide bond”, the entire trajectory of the chain can be defined by the pair of angles (for each AA): This can be represented with a “Ramachandran Plot”. From which it is obvious that there are some kind of clustering going-on. b al Protein structures are organized in a Hierarchical fashion a

  26. Periodicity To the delight of statisticians and computer scientists. Secondary structures – The alpha helix The Hydrogen Bond Again, a helix is an ideal setup to place our “velcro” H-bond always at the right place. Protein structures are organized in a Hierarchical fashion

  27. Secondary structures – The beta strand (beta sheets) Another periodical pattern ( ) Responsible for super-structure rigidity and some truly amazing patterns. Protein structures are organized in a Hierarchical fashion

  28. Secondary structures – The myth of “random” coil. Random structures in protein are extremely rare. Many uses the expression anyway to refer to the “rest” of the protein. Other minor secondary structures Turns, loops, bridges. Although these don’t have the critical periodicity found in a and b structures. Protein structures are organized in a Hierarchical fashion

  29. Tertiary structures – The reason why to care about 2nd structures. Secondary structures are building blocks Detecting and predicting secondary structures is a key process in structural biology. Other uses Visualization, classification… Protein structures are organized in a Hierarchical fashion

  30. Protein Diversity The current release of PDB contains 28,000 structure entries. 26,000 are proteins There is an estimated 600-8000 possible unique protein folds. http://www.jacquesdeshaies.com/expositions/virtual/new-virtual/uppsala-invit.html

  31. Overview Repository of structures Proteins, Nucleotides, complexes, mutants Quality improve over time Data validation tools are getting better. More redundant structure are available for cross-reference. PDB

  32. Small number of folds Does this means that all proteins are coming from a small set of ancestor molecule? Perhaps, but not necessarily.

  33. Protein folding Process of folding Modeling the process of folding Evolution vs. folding Impact of function on protein evolution

  34. Process Local Interactions Secondary Structure Elements (SSE) Assembly of SSE Equilibrium Structure

  35. Protein folding http://www.blueprint.org/proteinfolding/trades/details/trades_movies.html

  36. Protein folding Important thing to note It is possible that residues that are not doing anything in the folded protein were actually critically important to get the peptide folded in the first place.

  37. Protein folding Simulation studies are demonstrating that the most common protein folds are those who can withstand the most sequence variation over time without affecting their topologies. The prion protein is a posterchild example of the opposite.

  38. Protein Evolution Evolutionary meaning Most common folds are those able to withstand point mutations the best. These are known as designable folds.

  39. Protein folding Marginal stability The most stable folds are not necessarily these with the lowest energy. But these that maximally penalize switching to an alternative conformation.

  40. Protein Evolution Marginal stability Evolutionary implication(s) There is thus selective pressure on residues in protein not only to maintain important interaction, but also to make sure that some interaction NEVER happen.

  41. Summary Proteins fold into energetically stable conformations. For one chain, there are a large number of possible conformations, however. The biological conformation is selected during folding: not necessarily the “best” conformation.

  42. Role of biology on structures A few examples using mapping of rate of evolution. The fitness of a protein is ultimately its biological function, not its structure. We’ll have a look at their structural requirements.

  43. Fast Slow Rhodopsin-like G-protein receptors Pfam (dataset 1Tml_7) 69 taxa Maximum-Likelihood Site-Rates are Biologically Relevant

  44. Fast Slow Maximum-Likelihood Site-Rates are Biologically Relevant Tubulin a 34 taxa b 33 taxa The constraints imposed by co-evolution far outweigh the structural constraints.

  45. Phylogenetic mapping of structures Predicting rates of evolution This experiment was conducted to see if we could predict the rate of evolution in the enzyme Enolase.

  46. Phylogenetic mapping of structures Predicting rates of evolution The most important factor to predict evolutionary constraints was the presence of the active site. Evolutionarily constrained by the active site.

  47. Summary Structures are rigid templates to provide some biological function. It takes a lot of structure to position a few atoms in an enzyme.

  48. Structural Homology Because 1 structure is made of thousands of coherent interactions: The probability to see a new structure emerge from a random sequence is close to 0. Therefore: similar structures are likely to be homologous.

  49. Use of structural similarity in evolutionary studies Homology can be detected via sequence identity Structures are drifting at a much smaller rate. In fact, are they drifting at all? Structural similarity can be used to detect homology, although there are evidences that convergence is much more common in structure than sequence.

  50. Structural Convergence There are so many different ways to fold a dozen of secondary structure elements. Some fold are much more probable to evolve because they are more robust to mutations. Designability