Georgetown College. Georgetown University.

Visualization programs did not exist when Dr. Toshiko Ichiye first began studying molecule movements. Instead, she had to calculate the position of each individual atom as a function of time, producing reams and reams of data in the process.

Now Dr. Ichiye, the William G. McGowan Chair in Chemistry at Georgetown, is a leader in the field of molecular dynamics simulations, an area of computational chemistry that enables pharmaceutical companies, biotechnology firms, and bioengineering firms to design and perfect their products. Her computer simulations apply Newton’s laws of motion to the various tiny atoms that compose molecules. Dr. Ichiye and others in her lab predict the movements of atoms in sequential snapshots of time. This snapshot is almost unimaginably brief: just one femtosecond, or 10^-15 seconds; one trillion of these snapshots equals one second. Putting these snapshots together creates a simulation of molecular motion, much like sequential frames of a movie together create a visual image of motion.

Dr. Ichiye, then a graduate student in Dr. Martin Karplus’s laboratory at Harvard University, helped to develop a software program called CHARMM (Chemistry at Harvard Molecular Mechanics). CHARMM performs molecular dynamics simulations by calculating the positions of the atoms at each snapshot of time using Newton’s equations and simple properties of atoms such as: only one atom can occupy a single location at any given moment; atoms have positive or negative charges, and when two atoms each have a positive or each have a negative charge, they will repulse each other, but one atom with a positive charge will attract an atom with a negative charge; and chemical bonds between atoms cause them to move together, much like two people holding hands.

With the advent of sophisticated computer graphics, the molecular dynamics simulations from CHARMM can now be animated to make movies of molecules in motion.

“The whole protein was undulating together in a subtle way, while individual atoms were flipping back and forth,” says Dr. Ichiye, describing the first time she saw a graphical simulation of a protein.

 “My favorite part of research is taking all the data and putting it together so that I can explain a phenomena, somewhat like putting the pieces of a jigsaw puzzle together to get the whole picture,” she says. “Also, I like deriving equations that govern the behavior of various phenomena.”

At Georgetown, Ichiye uses molecular dynamics simulations from the CHARMM program to focus on questions related to biology, especially protein molecules.

“I have always had an interest in how physics can be used to explain natural phenomena and also in the complexity of how life works,” Dr. Ichiye says. “The research I do uses methods from physics to explain biological phenomena.”

One protein she studies is ferredoxin, which contains iron. Ferredoxin is involved in processes related to energy transfer and delivery in the mitochondria of cells and in chloroplasts in plants. Energy is transferred rapidly in cells as electrons move quickly from one metal site to the next site in a chain of adjoined proteins, called an electron transport chain.

Electron transport happens very quickly: In a protein such as ferredoxin, electrons hop from one site to the next at a rate of 10⁶ hops per second. The structure of the protein is relatively rigid compared to solution, which permits rapid hopping much like running on a hard surface is easier than running in sand. Electron transport must be a rapid process in order for cells, and whole organisms, to survive.

Dr. Ichiye says her most significant finding concerns metalloproteins, which are proteins with metals attached to them. These proteins play essential roles in respiration, photosynthesis, and many other important biological processes. She and her co-researchers have found that when metalloproteins have similar shapes or “folds,” their metals have similar properties, but when they have different folds, their metals can have vastly different properties. Moreover, the properties of the metals can be fine-tuned by the protein atoms near the metal. This also means that a mutation in a metalloprotein can cause a genetic disease by altering the properties of the metal. Conversely, mutations can be introduced into a metalloprotein to optimize the properties of the metal for a bio-electronic device.

Bio-electronic devices are just one application of the computer modeling she helped develop. Biotechnology or bioengineering firms can use the simulation models in developing new proteins that have been altered by mutations to produce a change in electron transport rate, for example. Pharmaceutical companies interested in designing new drugs can also use the computer simulations. Because the electron transport chain plays a key role in photosynthesis in plants and respiration in animals, potential applications are almost limitless.

Dr. Ichiye’s predictions can be more accurate than other approaches that look at only a limited set of interactions within a molecule because she considers interactions between all of the atoms in the entire protein. Her models also account for competing energies within a molecule.

“The fun thing for us as computational chemists is that we can make predictions from our models and then ask experimentalists to test those predictions,” she says. In many cases, follow-up experiments have demonstrated that the predictions of the Ichiye lab have been correct.

Dr. Ichiye also studies theoretical and molecular aspects of water using computer simulations. She and members of her laboratory published three papers in one year in the Journal of Chemical Physics on the dynamical properties of water and she was recently awarded a four-year, $639,000 grant renewal from the National Science Foundation to advance these studies. She has also received a $1 million grant renewal from the National Institute of Heath to continue studying electron transfer in iron-sulfur proteins using molecular dynamics computer simulations.

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