The aspartic protease of human immunodeficiency virus (HIV-1 protease) forms a c

Question

The aspartic protease of human immunodeficiency virus (HIV-1 protease) forms a complex of two identical proteins that can cut newly synthesized viral polyproteins into the mature, functional units that allow HIV to reproduce itself within host cells. If HIV-1 protease is inhibited by small molecules that compete with substrate binding within the active site (depicted with spheres in the figure), the nascent virions cannot go on to attack other cells, stopping the spread of HIV. Your task is to use your understanding of amino acids and weak interactions within proteins to characterize the active site of a mutant HIV-1 protease and predict the interaction of a new drug that can inhibit it! Shown below is a schematic of the active site of the HIV protease mutant. Note that because the functional form of the protease is a dimer (a complex of two identical proteins), the different amino acids belonging to each protein (A or B) are designated by an ‘A’ or ‘B’ under the amino acid one letter code and number.

Please answer the following questions (Parts 1-4):

1. Give the full names of the amino acids (shown as spheres) in the active site surfaces S1, S2, S3, and S4. You can simply add these to the diagram. (2 marks)

2.Beside each sphere, use small stick diagrams to draw the side chains (R-group only) of each amino acid that forms the active site pocket. Draw then so they project into the middle of the pocket. (4 marks)

3. Determine the net charge for each sub-pocket (S1, S2, S3, S4) at physiological pH (7.4)? (Hint: Determine the charge of each R group in S1, S2, S3, S4 and then give the net charges for each sub-pocket. You can assume that there are no free polypeptide chain ends in each pocket.) (4 marks)

4. Shown below is the chemical structure of the new HIV-1 protease inhibitor. Using your knowledge of weak chemical interactions, re-draw the inhibitor within the active site above in the orientation that would form the most favorable interactions to cause inhibition. (Hint: Match the four functional groups of the inhibitor (colored yellow) with the correct sub-pocket (S1, S2, S3, S4)). (2 marks)

Explanation / Answer

1. In surface S1, G48-Glycine 48

A28- Alanine 28

D30- Aspartic acid 30

V32- Valine 32

In surface S2, G49- Glycine 49

P81- Proline 81

V82- Valine 82

In surface S3, A28- Alanine 28

H29-Histidine 29

V32-Valine 32

G48-Glycine 48

For surface S4, F27- phenylalanine 27

V28- Valine 28

P81- Proline 81

G49- Glycine 49

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