The goal of this research is to understand the structural dynamics of muscle contraction and regulation, and to determine how the results can inform the development of therapeutics. The group is studying both force-generating proteins (actin and myosin), and their regulation by calcium pumps (SERCA) and channels (ryanodine receptor), which control the contraction and relaxation of the muscle by calcium uptake and release into the sarcoplasmic reticulum. In addition, they also study calcium binding proteins (calmodulin and calsequestrin). In recent years, the researchers have been involved in drug discovery projects to find small molecule effectors of muscle protein function. Structural and functional models, derived from structural information from X-ray crystallography and electron microscopy, are tested experimentally by an approach based on site-directed labeling and EPR and fluorescence spectroscopy. Specifically, structural models of conformational transitions in muscle proteins are tested and refined by results from the spectroscopic techniques with the aim to detect biologically relevant protein motions. No single method can provide needed information about changes in structure and interactions that occur under functional conditions; a multidisciplinary approach is needed. This approach includes computational simulations, which are necessary to connect atomistic models with experiment.
The group's main use of supercomputing resources is to perform atomistic microsecond-long molecular dynamics (MD) simulations. They have applied MD simulations to study the effect of ligand binding on the domain dynamics of SERCA. Other computational methods used include ab initio quantum chemistry calculations of spectroscopic probes and molecular dynamics simulations of proteins labeled with these probes. From these simulations, the researchers can determine parameters that can be used to interpret in a structural context experimental data from fluorescence and EPR spectroscopy. The simulations and experimental data suggest that large-scale open-to-closed functional conformational transitions occur. From these simulations thermodynamic properties important for the understanding of the protein function have been determined.