The Basics of Biophysics

Scheraga and his team are both theorists and experimentalits who study the way a protein should fold, based on their knowledge of fundamental physics. They allow a structure to grow and change in a computer model and calculate the potential energy of the molecule, repeating the process and looking for the best among an endless landscape of solutions.

This team is solving the multiple-minima problem, which is much like searching for a needle in a haystack. Remember, there isn't one answer to the problem; instead, they find the best among many answers, or the global minimum. Once you begin to deal with interesting biomolcules, it becomes impossible even to calculate all possible answers. Instead they use random methods intelligently guessing their way toward the best answer. If their equations are right, then the solution, the global minimum, will be the structure most likely to occur in nature, the native conformation. This is one of the fundamental measures of their success.

The power of Scheraga's approach to modeling protein folding rests in its reliance on math, not estimation. The number of calculations needed to find the global minimum solution grows exponentially with the addition of each link in the chain, as you move from a single amino acid to a chain, or polypeptide, to a full-blown protein molecule. Even supercomputers cannot yet handle whole enzyme molecules using this method.

Working within the constraints of their resources, the best in the world, and their model system, a well-known amino acid, Scheraga is able to refine the fundamental understanding of the physics of protein folding. He is refining the measures and tools used by others studying larger systems and designing new molecules.

Answers in 3D: Spin the end groups of this molecule and you will see that solving the puzzle of molecular conformation is not simple. Computer simulations will generate as many "right" answers as you like. This model is linked to the results of a simulation of the energy levels for one alanine in a polyalanine chain.

Calculation of the energy level is based on the rotation of two bonds: the bond between the nitrogen (blue) of the amino group and alpha carbon (green) of the backbone and the bond that connects the alpha carbon with the carbon of the carboxl group, shown here as carbon and oxygen bonded to the nitrogen (transparent blue) of the next chain.

As you spin the atom groups in the model, you change the values used in the calculation of the energy of the molecule. The energy for the shape you choose is shown on the graph. Blue areas contain "wells" of good, or low energy, solutions. The trick is to find the deepest point in the deepest well. Double click on the graph to get a closer look.