by Theresa Pepin
Genes may get all the glory, but proteins are where the action is.
Our ability to understand the dynamic motions of proteins is what really counts when we peer into biological systems and observe how they respond to change. Increasingly complex studies of protein systems—as they change shapes to regulate and signal biological processes—hold enormous promise for advances on many research fronts.
In collaboration with ORNL experimenters using world-class neutron technology and supercomputing facilities applied to the signaling protein, kinase A (PKA), Tongye Shen targets the challenge of studying complex protein systems with a powerful combination of modeling, theoretical, and computational tools.
From the point of view of physics, the functions of protein molecules—and whether they act for good or ill—relate to the changing of states or configurations of those molecules. That is, how they function in a biological system depends upon how stable each configuration is and how fast the molecules make transitions between configurations. Each molecule has multiple stable configurations (or “conformations”) and a range of simple to complicated dynamics (or “conformational” dynamics).
Modern biology identifies many diseases as malfunctions at the molecular level of protein systems. Thus, understanding the mechanisms of these macromolecules is of critical importance to the bioengineering of new diagnostics and therapies for diseases.
As a biophysicist Shen’s expertise is grounded in statistical and soft-matter physics and advanced computation. This project gives him the additional opportunity to collaborate in a multidisciplinary study of the large-scale, dynamic motions of signaling proteins using the cutting-edge technique of small-angle neutron scattering (SANS). However, we need better ways to interpret the valuable SANS observations related to flexible, large-scale motions of a signaling protein complex.
Enter Shen’s team—including post doc Ricky Nellas and undergraduate Richard Linsay—with “coarse-grained” modeling. The method sacrifices detailed information for the positive advantage of extending both the spatial scale (in terms of size or extent of dynamic motion of the signaling protein) and the time scale. While the calculations are formulated to take less than a few minutes, the approach is sensitive to small perturbations and void of sampling errors.
The complementary LDRD project headed by William T. Heller examines conformational changes in PKA with SANS and is an ideal testbed for validating and applying Shen’s statistical modeling tools to biomedical research. High-performance computer simulations led by Loukas Petridis will complement the joint effort. Both teams expect to continue their multidisciplinary collaboration both at UT-ORNL and with researchers at other institutions such as the University of California-San Diego and the University of Utah, while pursuing funding for further coarse-grained study of the dynamics of protein in complex environments and interfaces.
Coarse-grained modeling of the conformational dynamics of signaling protein complex
Tongye Shen, UT Biochemistry and Cellular and Molecular Biology Department, UT-ORNL Graduate School of Genome Science and Technology, and UT-ORNL Center for Molecular Biophysics
Probing the structure-function relationship in protein kinase A
William Heller, ORNL Biology and Soft Matter Division