The long term goal of molecular approaches to biology is to describe living systems in terms of the laws of chemistry and physics. The objective of this proposal is to use theoretical methods to increase our understanding of certain molecular machines that play a vital role in the function of living cells. The three systems that will be studied are ras p21, GroEL, and the F1 portion of ATP synthase. Ras p21 is an enzyme involved in regulating cell growth via a conformational transition from the active GTP bound form to the inactive GDP bound form; we will elucidate the mechanism by which GTP and GDP stabilize the different structures. GroEL is the experimentally best characterized chaperone, which plays a role in protein folding in E. coil and undergoes a large conformational change regulated by ATP binding and hydrolysis; we will determine how ATP binding leads to the conformational transition and how the conformational transition may act to unfold misfolded proteins. F0F1 ATP synthase is responsible for the synthesis of ATP, the mechanism involving differential binding of ATP and ADP to different conformations of the catalytic subunits will be investigated and the induction of the conformational change of the B subunits by rotation of the y-subunit will be simulated. For all three systems, free energy simulations and other molecular dynamics methods (e.g. targetted molecular dynamics) will be used in the investigation. The comparison of wild type and oncogenic mutants of ras p21 will aid our understanding of their role in cancer.
Showing the most recent 10 out of 22 publications
