Electric-Field Stimulated Protein Dynamics

A major goal in biomedical science is to move beyond static images of proteins and other biological macromolecules to the internal dynamics underlying their function. This level of study is necessary to understand how these molecules work, to engineer new functions, and to rationally develop therapeutics. Work in the past few years has finally enabled new nascent technologies for observing intramolecular dynamics in proteins and other biological macromolecules. In this application, we propose to advance a particularly exciting approach called Electric-Field Stimulated X-ray crystallography (EFX). EFX involves the use of large external electric fields to induce subtle motions within proteins and other biological macromolecules and to simply watch the resulting motions with atomic resolution and over a range of timescales in which motions are functionally relevant. This method has the potential to map protein mechanisms with unprecedented detail, but requires significant further work to broaden its application and to make it accessible. In this proposal, we describe the key advances – hardware, software, and computational – that can achieve these goals. We will install and test new machinery to generalize the method and will calibrate the size and orientation of the forces applied by electric fields at local environments within molecules. We will develop a modern, open-source, end-to-end software pipeline for reduction and analysis of raw data and will simplify the process of making biological interpretations. Finally, we will advance computational simulations that can work together with experiments in a virtuous cycle to fill in and extend the experimental analysis. Taken together, the work proposed here will enable the scientific community to practically use of the EFX method as a general tool for understanding proteins and other complex biological macromolecules. Project Number: 1R01GM163190-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: VUKICA SRAJER | Institution: UNIVERSITY OF CHICAGO, CHICAGO, IL | Award Amount: $2,506,748 | Activity Code: R01 | Study Section: Macromolecular Structure and Function B Study Section[MSFB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11278989