Doeke R. Hekstra

Scholar: 2018

Awarded Institution
Assistant Professor
Harvard University and Harvard School of Public Health
Department of Molecular and Cellular Biology


Research Interests

Towards Mechanical Understanding and Control of Proteins

My work seeks to understand how evolution gives rise to material organisms. In biology, we have a patchwork of explanations for why things are as they are, based on two kinds of causes: physics and chemistry on one side, and evolution on the other. I want to describe the interplay of these forces. Proteins are perfect model systems: they arise from evolution, yet their physics are experimentally tractable. I am working to address a crucial aspect of their physics that has been hard to study: coordinated motions of amino acids enable the functional transitions of proteins, but we cannot measure how these moving parts couple to each other. This is a question of mechanics—what are the coordinated motions, and which interactions guide them?

Previously, my colleagues and I showed that protein crystals tolerate electric fields strong enough to drive such motions within proteins, and that we can visualize these motions using short, timed X-ray pulses. The observed motions were natural, occurred throughout the protein, and were suggestive of their roles. We call this technique electric-field-stimulated X-ray crystallography, or EF-X.

We are working to establish EF-X as a method to characterize the mechanical principles which proteins use to perform essential roles in the growth of human and bacterial cells. We are particularly interested in the propagation of forces and motions between distant sites on protein surfaces. This phenomenon, allostery, plays a crucial role in the control of function of many proteins, both by nature, and by designed allosteric drugs.

To enable this work, we will further increase the ease, range, and accuracy of EF-X. The proposed work will hopefully make it possible to study how the mechanics of proteins depend on their evolutionary past, and to improve on previous efforts to design proteins with novel catalytic or mechanical properties.