The ultimate goal is to extend the capability of currently available methods to study the structure and mobility of all biologically important macromolecules, including those embedded in membranes or large molecular machines.
Our research is focused on developing new techniques and approaches for determining the structure and dynamics of bioactive molecules. We have four primary areas of interest that are detailed below.
Our first area of interest is in improving the accuracy of biomolecular structures determined by nuclear magnetic resonance (NMR) data. We are especially interested in developing the following: (a) better measurement techniques for interproton distances and dihedral angles from nuclear Overhauser effects (NOE) and J couplings, and (b) a quantitative relation between molecular structure and chemical shift(s) anisotropy.
Our second area of interest is in characterizing long-range intramolecular order by the measurement of dipolar couplings and rotational diffusion anisotropy. The methods we are developing address the main shortcoming of conventional NMR methods—the fact that they provide strictly local structural constraints.
Our third area of interest is in using NMR methods to study the relation between protein mobility and function.
Our fourth area of interest is in developing NMR technology that facilitates the structure determination process and makes it applicable to larger molecular weight systems. Effectively, our aim is to integrate de novo modeling approaches with sparse or easily accessible experimental data, including chemical shifts and amide and methyl group NOE data.
Further technological improvements are needed at all levels, ranging from very fundamental issues such as the relation between chemical shift and local structure, enhanced methods to extract chemical shift and other structural restraints from complex NMR spectra, to the development of computationally sophisticated procedures at the interface between molecular modeling and classical experimental structure determination. Together, this will expedite the process and extend its applicability to ever larger and more complex systems.