Scientists have used computational simulations to observe geometry optimization of molecules like proteins and to calculate the free energy differences between two molecules. Most simulations encounter large energy barriers that prevent the observation of a folded protein accurately or that prevent the calculation of absolute free energies. With methods developed in the lab of Dr. Ralph A. Wheeler, I will predict the correct folded structure of a protein and will calculate not only the relative free energy differences between molecules, but the absolute free energy of a molecule. First, I will test the geometry optimization method on dialanine, divaline, an a-helical polypeptide and a b-sheet polypeptide. I will extend the tests on prion proteins observing the folding of the mostly alpha-helical protein to the beta-sheet dominant protein. I will test the free energy calculation method with small organic molecules, dipeptides, and helix-forming and sheet-forming proteins. The tests will be extended to point mutations of the prion proteins calculating the propensities of the protein. Finally, calculations will be done to find the binding free energy differences between molecules bound to the prion protein. Through these simulations, drugs could be designed to combat the prion disease. Such possibilities include the stabilization of the a-helical form or the prevention of aggregation after the b-sheets are formed. ? ?
