Collaborative Research: Tackling Functional Protein States at Atomic Detail by Integrating Weighted Ensemble Simulations with Magnetic Resonance Restraints

This project is designed to characterize the alternate structures of proteins—the workhorses of life whose functions in biology are determined by their structures. A major challenge to characterizing these so-called “functional structures” is that these structures are often too diverse or fleeting to be captured by experimental techniques at the level of individual atoms.

An unmet need is therefore a strategy that can determine the structures of functional protein structures at the atomic level and even more crucially, a strategy that can provide insights into how the functional structures interconvert. This project will develop a new software tool that can determine the functional structures of proteins, how the proteins move to convert from one structure to another, and the rates at which the structures interconvert.

This tool combines the use of computer simulations with distances within proteins that are measured by experiments and will be made available through a popular, freely available WESTPA simulation software package. This interdisciplinary, collaborative project is providing a valuable training ground for graduate and undergraduate students participating in the research, and is supporting diverse educational and outreach activities, including biennial WESTPA software workshops to provide training to the scientific community in using the new tool for determining the functional structures of proteins.

A new frontier in biophysics has been the structural characterization of protein functional states. Proteins are the workhorses of life and their functions are determined by their structures. A major challenge to characterizing protein structures is that many proteins adopt not just a single structural state, but alternate states that are relevant to the biological functions of the proteins.

Due to the diversity and often transient nature of such functional states, the determination of their structures at the atomic level has been elusive to experimental techniques. An unmet need is therefore a strategy that can generate atomically detailed structures of functional states, and even more crucially, a strategy that can provide detailed insight into the pathways for interconversion between the states and corresponding kinetics.

A key advance of the project is the development of a general strategy that integrates sparse distance restraints from magnetic resonance experiments with rigorous simulations to provide atomic level structures and dynamics of functional protein states. This project will provide a new simulation tool that will be made available to the scientific community through the freely available WESTPA software.

To further enhance the accessibility of the software, the WESTPA software will be integrated with the Orion cloud-computing platform on Amazon Web Services, the world’s largest on-demand, cloud-computing facility. This project is funded by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences, with partial co-funding from the Chemical Measurement and Imaging Program in the Division of Chemistry.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.