Our understanding of the structure:function paradigm for proteins has shifted in recent years, recognizing that disordered proteins and flexible assemblies are highly abundant in cells and play central roles in biological function. These systems are particularly challenging because they cannot be studied using widely available structural biology techniques such as crystallography, nuclear magnetic resonance spectroscopy or cryo- electron microscopy. We are developing new integrative approaches and technologies are needed to characterize disordered and flexible systems. Small-angle neutron scattering (SANS) is ideally suited to studies of flexible and disordered proteins, and large dynamic complexes. The specific labeling that is observable with neutrons and enabled by deuteration enhances the visibility of specific parts of complex and dynamic assemblies. Combining SANS with computational modelling can thus provide unique structural information that is unattainable by other means.
Developing physical models of disordered proteins and flexible dynamic assemblies is uniquely challenging because these systems typically exist as an ensemble of conformational states. We address the two main computational challenges facing molecular dynamics (MD) simulations: obtaining adequate sampling and employing reliable force fields. Running scalable MD codes that harvest the immense computational power of ORNL provide enhanced sampling. The MD models are validated by calculating SANS structure factors and comparing directly to experiment. Integration of experiment and MD simulation involves the use of simulation to guide experimental design, as well as SANS data to refine the simulation results.