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Problem Set 3 the Problems I Ask You to Work Through in This Problem Set

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Problem Set 3 the Problems I Ask You to Work Through in This Problem Set Problem Set 3 The problems I ask you to work through in this problem set cannot be handed in, in any form. This does not mean that the topic of this problem set is not important !!!! It simply reflects the fact, that hands-on building of molecular models is a much better way of learning about molecular structure than looking at powerpoint slides. So grab your model building kit, a text-book with a picture of an alpha helix, a beta- sheet and a Ramachandran plot and go to work. Problem 1 a) Start by drawing out a peptide backbone on paper. How many different types of covalent bonds do you encounter as you walk along the backbone? In the drawing indicate the bonds, around which rotations can occur and which of the rotations are described by the phi and psi angle? Are there bonds that cannot rotate? Why? b) Built a bunch of amino acids using the long green tubes to represent the side chains. Make sure that you are building L-amino acids (remember the CORN rule). c) Built a molecule consisting of an alpha carbon, a side-chain and two peptide bonds. Identify the torsion angles that correspond to phi and psi. Adjust phi and psi and measure the atomic distances between atoms separated by more than two bonds. (Use a metric ruler to get a feeling for the distances. In the models I gave you 20 mm correspond to ~1Å). Compare your observations to the Ramachandran plot. d) Link some amino acids (~12) up to a linear fully stretched-out peptide. What are the phi and psi angles? Is this fully stretched conformation exactly the same as that found in a beta strand? Compare your peptide to the pictures of beta-sheets found in the textbook. Now make a beta-turn and fold the chain back onto itself to get a sheet. Where do the sidechains point? What is the spacing of the hydrogen bonds? Are they evenly spaced? e) Now take our peptide chain and try to fold it up into a helix. Initially try to simply adjust the model until you get a helix. You will probably find that to be rather difficult! Now use the phi and psi angles to build your helix. What are those angles? If you don’t remember from class, look them up in the Ramachandran plot. Here are some checks that you really got a helix: i) check that the helix is right-handed (i.e. if you stand the helix on end and you would walk up the backbone in counterclockwise direction, you should be walking uphill. Btw this works independently of which end of the helix is up) ii) The hydrogen bonds should be formed between residues i and i+4 (i.e. 1-5, 2- 6 etc. Make sure when you are counting to keep track of which nitrogen and oxygen belongs to which amino acid.) iii) The side chains should be pointing to the N-terminal end of the helix. iv) Try to see the two types of ridges and the “knobs and holes” formed by the side-chains on the helix. Visualize how they would fit into one another. Problem 2 We went through this quickly in class, but it is worthwhile working through this problem again on your own. In the helices of naturally occurring proteins beta-branched amino acids are found much less frequently than you would expect statistically. Also, in model peptides that have a propensity to forming alpha helices incorporation of beta-branched amino acids destabilizes these helices. Use your molecular model of an helix to understand where this effect is coming from. This is a nice exercise that allows you to put together a lot of themes I tried to highlight in class: Packing, molecular crowding, conformational entropy etc. etc. a) Built a valine and a methionine side chain and place them on one of the alpha- carbons in your helix. Start with the methionine. Rotate the c-alpha-to-c-beta bond so that you get the proper staggered arrangement of the three other atoms bonded to the C-alpha and C-beta carbon. There will be three staggered conformations. How many of these three conformations around this bond can you adopt while avoiding clashes between the side-chain atoms and the helix backbone. b) Now take the valine side chain and do the same thing. How many of the three rotamers can you adopt? How much of a difference in entropy results from the difference in the number of configurations. c) Now consider the case of a helix that is part of a protein and there the face of the helix that contains the methionine or the valine actually faces into the interior of the protein. If in both cases the environment restricts the conformation of the side chain to one conformation, does beta-branching still destabilize the helix? Why not? Problem 3 Try to answer this question without looking at the helix you just built. a) What are the characteristic features that identify an alpha helix? (e.g number of residues per turn, where do the side chains point, what is the hydrogen-bonding pattern, what is the handedness of the helix b) etc etc.) c) Using the criteria you identified above, which of the 5 poly-alanine helices shown below are real alpha helices? For those helices that are not real alpha helices identify the features that make them “wrong”. (e.g. D- instead of L- amino acids, too many or too few residues per turn etc.) d) Alpha helices have an electrostatic dipole moment, but beta sheets do not, explain why. .
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