fossils Biochemistry major Lysandra Sola '01 created this computer model of an HIV protease, represented by the ribbon-like structure, with a bound inhibitor (purple).

A Look Inside the World of Molecular Modeling
Professor Philip Borer seats you in front of a Silicon Graphics computer, hands you a pair of stereoscopic glasses, and punches a few keys. Suddenly you’re peering in 3-D at the inside of a simulated molecule, exploring its structural intricacies. “Computer modeling has an immediate visual impact,” says Borer, professor of chemistry, biophysics, and biophysical chemistry in the College of Arts and Sciences. “These models are more than elaborate cartoons. They can be used to highlight important features and illustrate interactions.”
      Borer and chemistry department colleague James Dabrowiak help undergraduates navigate the biomolecular world in the two-course sequence Structural and Physical Biochemistry I and II. In the first course, which focuses on structural biology, students tackle molecular modeling on computers similar to those used by pharmaceutical companies. They learn bonding concepts and build biochemical structures using specially designed software and the Protein Data Bank, an Internet-based international repository containing thousands of protein structures. In the second course, students investigate molecular thermodynamics and equilibrium, kinetics, and statistical mechanics, using advanced modeling to study, say, how enzymes accelerate rates in reactions or how random meetings among combinations of molecules have certain statistical probabilities. “We’re bringing computer modeling not only into the structures and their relative energies, but also into the kinetic and statistical effects presented in these courses,” Borer says.
      Borer and Dabrowiak furthered that goal recently with a $25,000 grant from the Dreyfus Foundation. This summer, the grant funded the research of two undergraduates—Lysandra Sola ’01 and Beth Vesey ’00. They worked on projects incorporating dynamical and statistical effects into future modeling exercises for the structural and physical biochemistry courses. Vesey studied molecular dynamics trajectory, simulating how a plant hormone jumps between different stable states over time—in this case, one nanosecond—to learn about the molecule’s transition frequencies.
      In her project, Sola analyzed the energetics of the interaction between an HIV protease, an enzyme found in the virus, and inhibitors bound to the protease to prevent replication. “HIV is a tricky molecule because it likes to mutate,” Sola says. “Once it mutates, the inhibitors don’t do anything, so it’s important to try to find new inhibitors.”
      Both students examined how a short peptide of amino acids folds into an alpha helix, a common structural motif, through a two-stage process of initiation and propagation. “On the computer you can alter the probability of initiation and propagation,” Borer says. “This will help students understand why an alpha helix zips up once it forms. In a population of molecules, most of them are either completely folded or unfolded. You almost never find intermediate states.”
      Ultimately, through their project, Borer and Dabrowiak plan to create an accessible Internet database of structures—Drugs and the Molecular Basis for Disease—linking disease information to entries for drug-biomolecular structures in the Protein Data Bank. Such collaboration is crucial as scientists make advances in this vast new field and turn to molecular modeling to help them understand and disseminate their findings. “The more technology improves, the better our chances will be of figuring out things in the lab,” says Sola, a passionate researcher. “Do I want to spend countless hours in a lab? Yes, I do.”
                                                                                                                                                                —JAY COX

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