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Kusai MerchantThe Wild Dance of Proteins:
Flexibility and the Connection Between Structure and Function

Kusai Merchant
Department of Chemistry
Stanford University
November 2002


Proteins come in all shapes and sizes, and these different shapes and sizes allow proteins to accomplish different tasks in the body. However, knowing the structure of a protein is often not enough to determine what a protein does or how it does it. Proteins are not rigid molecules, and different protein structures have inherent differences in flexibilities, which allow proteins to perform their functions. I use lasers to measure the flexibility of proteins in order to understand the connection between the structure of a protein and its function. Protein flexibility is the key link between its structure and function. Understanding this connection between structure and function will one day allow scientists to engineer new proteins to treat disease.

Myoglobin, the protein that I study, is responsible for the storage of oxygen in muscle tissue. In order for this protein to work effectively as an oxygen storing protein, it must be able to store excess oxygen in the cell, and release it later when the cell needs it. Myoglobin regulates the amount of oxygen in the cell by controlling the strength of its chemical bond with oxygen. When the concentration of oxygen is high in the cell, myoglobin makes a stronger chemical bond with oxygen causing a net absorption of oxygen, and when the concentration of oxygen is low, the chemical bond between myoglobin and oxygen is weakened, causing a net release of oxygen. Somehow, the protein is able to sense changes in the cellular environment, and then respond to these changes by making slight adjustments to its structure to control the rate of oxygen uptake or release to meet the changing conditions in the cell.

My research is focused on answering three questions: 1) what structural changes in myoglobin are responsible for controlling the binding rates for oxygen, 2) how are these changes in structure caused by changing cellular conditions, and 3) how do these structural changes affect the strength of the interaction between myoglobin and oxygen. All three of these effects involve motions of the protein. Because myoglobin is a relatively small protein with a simple function, it serves as an excellent model to develop and test basic ideas about the fundamental properties of all proteins. The key to answering all three of these questions is to understand how flexible is the protein, and in what ways. In this context, flexibility has two components, the range of motion, and the rate of motion. The ideal experiment would be to grab a protein, stretch it like a rubber band as far as it can go, then let it go and watch how fast it snaps back into place. Unfortunately, this type of experiment is not possible with the current state of technology. It is possible however to deduce the same information about the range and rate of motion of a single protein by watching a large number of them simultaneously.

To understand how this is done, imagine for a moment that instead of proteins, one is interested in measuring the flexibility of the human arm. A thousand people volunteer for this experiment, and each person is given a drum and a drumstick. Everyone holds their drumstick in their hand, and they all stand in such a way that as they bend and extend their arm, they strike their drums with their drumsticks. Everyone is allowed to beat their drums as quickly or slowly as they want, and to bend their arms as much as they want. However, they must all start beating their drums at the same time. The experimenter records the drum beat pattern with a microphone. When the start signal is given, everyone starts bending and extending their arms, and there is one sharp, strong, collective drumbeat because everyone is hitting their drums at the same time. However, after some time, everyone is beating their drums out of time because everyone is bending and extending their arms different amounts at different rates, and the one strong drumbeat becomes many continuous weak individual drumbeats. The experimenter then analyzes the recorded drumbeat and determines the rate at which the sharp, strong drumbeat turns into or "decays" into the continuous, weak, individual drumbeats. This rate of decay of the drumbeat is related to how far and how fast people bent and flexed their arms. If enough people participate in the drumming, then the flexibility of every type of arm and every beat rate is measured at once. The drumbeat decay rate is enough to extract information about the flexibility of the average human arm.

In my experiments, a laser pulse is used to stretch the bonds of the many myoglobin molecules in the sample causing them all to vibrate. This pulse is analogous to the start signal for the drummers. A little while later, a series of laser pulses are then used to "record" the decay rate at which the vibrations get out of sync with each other. This information is used to determine the flexibility of that part of the protein that was stretched. By stretching different parts of the protein, the flexibility of the entire protein can be measured. Performing these experiments with different cellular conditions allows us to determine how myoglobin responds to the cellular environment, and correlate changes in structure with changes in function.

The insights that are gained from studying the connection between myoglobin structural changes and oxygen binding apply generally to the connection between all protein structures and their functions. This type of general insight between the structure and function of proteins is one of the great challenges facing science and medicine today. The insights gained from the connection between protein structure and function opens the possibility of one day designing new proteins to fight and cure disease.