With this grant we propose to continue our work in the domain of protein structure determination by NMR. We have recently reported the construction of a novel computer program, PROTEAN, which simultaneously determines molecular structure as well as the uncertainty in the position of each atom within the molecule. We have also reported another program, BLOCH, which calculates the expected build-up curve for NMR Nuclear Overhauser Enhancement (NOE) measurements. We propose to build two new computer programs which will allow us to investigate the dynamics of proteins in solution with a view to more accurately predicting structures that will match the observed spectra. The first program, BLOCH*, will allow the prediction of the build-up of NMR NOE measurements from an uncertain protein structure. The novel aspect of this program is that it will use explicit estimates of the uncertainty of atoms within the molecule to predict not only the spectra expected from a rigid molecule, but also the spectra of a molecule which has differential uncertainty in the position of each atom. This will allow us to predict more accurate spectra that take into account the effects of positional uncertainty within a molecule. The second program, PROTEAN*, will produce models of protein dynamic motion which explain the observed NMR spectra. These models will be derived from three sources: the known chemical structure of the molecule, the uncertainty in atomic positions as calculated by our structure determination program, and simple simulations of where and how molecular motion can take place in a large molecule.
