1) The penicillin family of antibiotics, discovered by Alexander Fleming in 1928, has the following general structure: O O

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1 ame: TF ame: LS1a Fall 06 Problem Set #3 Due Friday 10/13 at noon in your TF s drop box on the 2 nd floor of the Science Center All questions including the (*extra*) ones should be turned in 1) The penicillin family of antibiotics, discovered by Alexander Fleming in 1928, has the following general structure: S Penicillin ("" = variable region) pka = ~2.8 (a) (4 points) The biosynthesis of penicillin makes use of two natural amino acids; identify them (they have been colored to assist you). (b) (2 points) Circle the amide bonds in the molecule. (c) (4 points) The p of blood is ~7.4. What is the dominant ionic form of penicillin found in the bloodstream? Draw your answer below:

2 ame: TF ame: The target of penicillin is a bacterial enzyme called a transpeptidase, which helps synthesize the bacterial cell wall. The enzyme is shown below, bound to penicillin (shown in purple): (d) (2 points) What type of protein secondary structure is exhibited by the region colored blue? (e) (2 points) What type of protein secondary structure is exhibited by the region colored red? The target of the transpeptidase is a sequence of 5 amino acids, attached to the sugars of the bacterial cell walls. The sequence is shown below: A C E (f) (5 points) Identify the 5 amino acids. B D 2 (g) (*extra*): What is unusual about the amino acids B, D, and E? ow are they different from the types of amino acids normally found in proteins?

3 ame: TF ame: Transpeptidation is the process of crosslinking two adjacent peptide strands to rigidify the bacterial cell wall: 2 2 Penicillin Transpeptidase ew "cross link" + Side product 2 By preventing cell wall synthesis, penicillin causes bacterial cells to rupture from osmotic pressure, thus killing them. (h) (3 points) Is the amide bond (boxed) in the new cross link normally found in proteins? Why or why not?

4 ame: TF ame: 2) BCA1 is a protein that is important in maintaining healthy breast cells. BCA1 is a large modular protein of 1,863 amino acids. The C-terminal end of the protein (amino acids 1,528-1,832) contains two amino acid domains called BCT (BCA C- terminal). This region is shown below. Shown below is a segment of BCT that it is important in the interaction between the two BCT domains (a) (11 points) Label the amino acids contained in this portion of the protein on the diagram above. (b) (11 points) Write the amino acid sequence using the one-letter code for the amino acids ( to C) (c) (4 points) What do the numbers underneath the peptide represent? (d) (8 points) Draw the peptide at physiological p (making sure to indicate formal charge!).

ame: TF ame: 3) The major interface between the two BCT domains is circled below in red and a blowup of the left and right helices of the interface is shown below (the backbone is shown as a thin

5 ame: TF ame: 3) The major interface between the two BCT domains is circled below in red and a blowup of the left and right helices of the interface is shown below (the backbone is shown as a thin ribbon and the side chains as sticks). Pro Lys Asp Arg Leu Phe Gln Leu Glu Tyr Trp Ile Leu Met Leu Val Gln Left helix Ala* Cys interface ight elix (a) (4 points) The interface between the helices is defined by the gray box shown above. What general type of amino acid is lining the interface between the helices? (b) (4 points) What are the forces that help stabilize the interaction between the BCT helices?

6 ame: TF ame: c) (8 points) Another important interaction occurs between the residue Arg on one helix and the residues, Glu and Asp, on another helix (not shown in the figure). Draw a possible interaction between the Arg, Glu and Asp side chains, and identify the nature of this interaction. 4) Mutations in BCA1 occur in 50% of women with inherited breast cancer. Many of the mutations that occur are single amino acid changes in the BCT domain. (a) (4 points) List at least two ways in which changing a single amino acid can affect the function of a protein. Please limit your answer to three sentences. (b) (4 points) ne type of mutation that causes breast cancer involves the mutation of an alanine at the interface between the two helices shown in the second figure of problem 2 (labeled as Ala*) to a glutamic acid. ow could this mutation disrupt the structure of the BCT?

7 ame: TF ame: 5) Vancomycin is an antibiotic that used in the clinic to treat bacterial infections. Vancomycin works by inhibiting bacterial cell wall synthesis, a process essential for bacteria. Shown below is vancomycin interacting with its target in the bacteria. (please note that this is a distorted 2D view of a real 3D structure. You can assume that target is closer to vancomycin than what is depicted.) 2 Cl Vancomycin Cl 2 2 Bacterial Target (a) (2 points) Using your knowledge gleaned from LSA, name the red molecules in the bacterial target. (b) (6 points) There are three types of interactions that bind vancomycin to its target. ne type is indicated by the dashed lines in the diagram above. A second type of interaction occurs between the -terminus of vancomycin and the C-terminus of the target. A third type of interaction occurs between the rings at the other terminus of vancomycin and one of the methyl groups on the target. Please name these three types of interactions.

8 ame: TF ame: Bacteria develop resistance to vancomycin by changing the structure of vancomycin s target from the one shown above to the following. Vancomycin cannot bind well to this target, and loses its ability to kill bacteria. (c) (8 points) Using the interactions between vancomycin and its natural target as a guide, draw in the interactions between vancomycin and this new target. ationalize why vancomycin loses binding affinity with the new target. 2 Cl Cl 2 2 The major difference between the two targets is boxed. natural target; bacteria killed by vancomycin new target; bacteria resistant to vancomcyin

9 ame: TF ame: (d) (4 points) Draw one resonance structure that you think would contribute significantly to the actual structure of the boxed region of the natural target. natural target; bacteria killed by vancomycin (*extra*) Draw one resonance structure that you think would contribute significantly to the actual structure of the boxed region of the new target. new target; bacteria resistant to vancomcyin (*extra*) Using the resonance structures that you drew, rationalize which target (natural or new) has more double bond character. (hint: think about the electronegativity of the atoms involved.

Basic concepts of molecular biology

Basic concepts of molecular biology Gabriella Trucco Email: gabriella.trucco@unimi.it Life The main actors in the chemistry of life are molecules called proteins nucleic acids Proteins: many different