lecture 7

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Biological Sciences 105 Lecture 7, October 23, 2018 Copyright Steven M. Theg, 2017. All federal and state copyrights reserved for all original material presented in this course through any medium, including lecture or print. 1 On to higher order structures How do we know proteins fold into unique structures? Early evidence came from the ability to crystallize a protein. In order to make a crystal, need to have many identical molecules. Therefore, even though have a large molecule (protein), it must have a single, unique structure. Why do proteins fold into unique structures? Take all possible conformations and calculate the change in free energy (  G) compared to the completely unfolded random coil. A plot of the folding pathway may look something like this: Final conformation is likely to be the global minimum energy configuration. The  G for the final folded structure is generally low, -20 to - 65 kJ/mol, which I call low compared to the -200 to - 400 kJ/mol for the formation of a single covalent bond. Most of the stabilizing force comes from the many small, non-covalent interactions discussed earlier. What’s the destabi lizing force? Answer is … Then the  G of stabilization is the balance between the large increase in Gibbs free energy due to entropy and the large decrease in Gibbs Free Energy due to the many weak interactions. Two general rules apply to protein structure: 1. Put the hydrophobic residues in the interior away from water, 2. the number of hydrogen bonds should be maximized. The four levels of protein structure: Primary structure is the amino acid sequence. Secondary structure is the residue-by-residue conformation of the backbone. Tertiary structure is the three dimensional conformation of a single polypeptide. Quaternary structure is the three dimensional structure of a multisubunit protein.

Biological Sciences 105 Lecture 7, October 23, 2018 Copyright Steven M. Theg, 2017. All federal and state copyrights reserved for all original material presented in this course through any medium, including lecture or print. 2 Secondary Structure - = local structure. Five distinct types Recall that the C-N bond has partial double bond character due to sharing of the e - in the O double bond. This constrains the rotation of the C with respect to the N. Planar. Can get rotation around the  carbon. A couple of residues look like this: Linus Pauling (who is this?) realized that short term interactions between nearby residues could result in hydrogen bonds. Number of different types of defined 2  structure. Not all rotations about the  carbon result in stabilizing H-bonds, nor are they all allowed. The angle  refers to the angle between the  carbon and the carbon of the  carboxyl (on the right), and the angle  refers to the angle between the  carbon and the nitrogen on the  amine (on the left). One representation of the shape of a protein backbone in 3D space is to give the position in 3D space of each of the atoms. But another, equally valid representation would be to give the position of the first atom, and then all the ψ an d  angles thereafter. This is sometimes used. 1. Right-handed  -helix . Many ways to draw.

Biological Sciences 105 Lecture 7, October 23, 2018 Copyright Steven M. Theg, 2017. All federal and state copyrights reserved for all original material presented in this course through any medium, including lecture or print. 3 Characteristics of an  -helix: 1. Rises 0.54 nm per complete turn 2. One turn goes 3.6 residues. 5.4 A/3.6 = 1.5 A/residue. 3. The R groups stick out of the helix center. They don't participate in the hydrogen bonds, but they do influence them. 4. Hydrogen bonds are formed between fourth residues. Go to the computer and show an α -helix in MbO. Rainbow color A, find polar, just main chan Select resn pro, sticks 2. Anti-parallel  -sheet.

Biological Sciences 105 Lecture 7, October 23, 2018 Copyright Steven M. Theg, 2017. All federal and state copyrights reserved for all original material presented in this course through any medium, including lecture or print. 4 Can create a continuous sheet of antiparallel  -sheet structure by having the protein loop back upon itself many times, like so; Go to the computer and show a  -sheet, 3. The turn region of the antiparallel  -sheet has a particular conformation, called a  -turn or  -bend . Go to the computer and show a  -sheet 4. Parallel  -sheet . Cannot be formed by adjacent sections of the protein, must be connected through distant regions. Like so;

Biological Sciences 105 Lecture 7, October 23, 2018 Copyright Steven M. Theg, 2017. All federal and state copyrights reserved for all original material presented in this course through any medium, including lecture or print. 5 5. Random coil Most other structures are commonly referred to as random coil . They are not necessarily random, but simply not one of usually defined 2  structural types. The different R groups influence whether a particular 2  structure is stable. If this were not the case, all proteins would be made of only  -helices  sheets. For example: Proline does not fit well into an  -helix because it has constraints on the rotation of the bonds coming from the  -carbon. Proline is a helix breaker. It also doesn't fit well into  -sheets, but does fit well in  - turns. Glycine's R group (H) is too small to exclude water from the backbone region, so it H-bonds to water instead of the residue 4 positions away. It is allowed in  -helices, but it does not stabilize them. The particular 2  structure finally adopted depends on a balance between stabilizing and destabilizing forces. Know many of the important forces, so can predict with some success different 2  structural elements from the 1  structure. There are numerous programs on the internet that do this, none of which are perfect.

Biological Sciences 105 Lecture 7, October 23, 2018 Copyright Steven M. Theg, 2017. All federal and state copyrights reserved for all original material presented in this course through any medium, including lecture or print. 6 Tertiary structure Most proteins are globular, with hydrophobic residues buried inside, away from water. The position of every atom in 3D space gives you the tertiary structure of the protein. Two general rules apply to tertiary protein structure: 1. Put the hydrophobic residues in the interior away from water, 2. the number of hydrogen bonds must be maximized. Show folding surface on computer. For a long time it was thought that the particular conformation a protein adopts is determined solely by its 1  structure, and that the 3  structure was achieved spontaneously. Self-folding and self -assembly. This is certainly true for some (many) proteins. However, Levinthal’s Paradox: Can protein randomly search for their global energy minimum? Take a protein with 100 aa’s. Assume there are only 2 conformations possible for each aa. Then there are 2 100 = 1.27 x 10 30 conformational possibilities. Allowing the conformations to be sampled at the speed of molecular vibrations, one for every 10 -13 s, then the time to test all the conformations is 10 -13 s x 1.27 x 10 30 = 1.27 x 10 17 sec = 4 x 10 9 years, which is about the age of the Earth. What? It is now known that many other proteins require additional factors in the cell to fold in the correct manner. Molecular chaperones. Folding pathways.

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