Section 1: Chemical and Physical Foundations of Living Systems

Passage 1(Questions 1-4)

HIV protease is an example of an aspartyl protease; an enzyme that utilizes an aspartate side chain during the catalytic cleavage of a peptide bond. Since HIV protease is a relatively small homodimer of a 99-residue protein, it can be directly synthesized, or cloned and expressed in fast growing cells. For this reason, it was targeted for structure-based drug design in order to treat HIV infection.
A portion of the peptide cleaved by HIV protease is shown in Figure 1.

Figure 1 The peptide bond cleaved by HIV protease
Using molecular models of the HIV protease enzyme, researchers designed and synthesized transition state analogs. One such molecule is Compound 1, shown in Figure 2, which is a potent HIV protease inhibitor.

Figure 2 Structure of Compound 1
Compound 1 has an in vivo half-life of 1.8 h and is primarily metabolized by CYP3A, an enzyme in the cytochrome P450 family. The major metabolite of Compound 1 results from dealkylation of CH2R groups attached to the piperazine ring system (Reaction 1)

Reaction 1
One of the main side effects of prolonged use of Compound 1 is the formation of kidney stones composed of calcium oxalate CaC2O4. Researchers used their knowledge of the HIV protease active site, and the metabolic pathways that lead to destruction of Compound 1, to design and synthesize several derivatives of Compound 1 in an effort to modify its properties and increase its potency and half-life.

Section 3: Biological and Biochemical Foundations of Living Systems
Passage 1(Questions 5-9)/b>

Proper bimolecular trafficking, including protein packaging by the Golgi apparatus, is essential to the compartmentalized eukaryotic cell. Therapeutic agents that disrupt the function of the Golgi apparatus reduce cell viability and can serve as effective treatments for carcinoma.

ADP-ribosylation factor I (Arf1) plays an essential role in vesicle formation and is responsible for the recruitment of the cytosolic coat protein complexes (COPs) and subsequent retrograde transport from the Golgi apparatus. Arf1 is activated by guanine nucleotide exchange factors (GEFs), which replace guanosine diphosphate (GDP) with guanosine triphosphate (GTP). Upon GTP exchange, Arf1 undergoes a conformational change that releases the myristoylated N-terminus of the polypeptide chain from a structural groove in the protein and initiates localization to phospholipid bilayers. Once associated with a bilayer, Arf1 further facilitates vesicle formation by the recruitment of the hetero-tetrameric (dimer of dimers) costumer protein complex βδ/γζ-COP1 (subunits are represented by β, δ, /,γ andζ). The Arf1 GTPase activating protein (GAP) catalyzes the conversion of Arf1- bound GTP to GDP and inorganic phosphate, thereby converting the protein to the inactive form. GAP activity is increased by Arf1 binding to βδ/γζ-COP1.

Brefeldin A (BFA), a lactone compound isolated from fungi, has been shown to inhibit Arf1-driven vesicle formation, resulting in reversible disruption of the Golgi apparatus and tumor revision in vitro. Because of its low bioacailability, BFA is not a suitable candidate for pharmaceutical deployment; however, it has led to the identification of AMF-26 as a promising drug candidate.

AMF-26 is predicted to bind to a protein-protein contact interface of Arf1, preventing GTP exchange by GEF and disrupting Arf1 membrane localization in the initial critical step of COP1 recruitment and vesicle formation. In clinical settings, oral administration of AMF-26 has led to remission of breast cancer xenografts in mice model systems.

Section 4: Psychological, Sociological, and Biological Foundations of Behavior
Passage 1 (Questions 10-14)

Researchers interested in the memory processes of Alzheimer patients conducted a study comparing Alzheimer patients to adults with normal memory. The participants were administered a list of 21 unrelated words, at the rate of one word every three seconds. Immediately after the presentation of the last word, the participants were asked to recall as many words as they could from the list. The Alzheimer patients were 60 to 80 years of age. Participants without memory impairment were dinvided into three age groups: 20-39, 40-59, and 60-80. After the recall task, the participants were given a recognition task.

The results of the study are presented in Figure 1.

Figure 1 Number of words recalled and recognized

he list of words was presented in the same order to all groups. The researchers were also interested in the percentage of total recall for words from different parts of the list. More specifically, they analyzed the percentage of each group’s recall from the beginning, middle, and end of the list. The results are presented in Figure 2. The performances of 20-39 and 40-59 year-old groups did not significantly and are combined into one group.

finding that emerged from the recall task was the participants without memory impairments retrieved words that were related to the words on the list but had not actually appeared.

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