Conformational Disorder of Proteins Assessed by Real-Space Molecular Dynamics Refinement

Abstract

Motion is critical to the function of many proteins, but much more difficult to study than structure. Due to lack of easy alternatives, although there are inherent limitations, there have been several prior attempts to extract some information from the Bragg scattering in conventional diffraction patterns. Bragg diffraction reflects only a small proportion of a protein's motion and disorder, so fitted values likely underestimate reality. However, this work shows that the fitted estimates should be even smaller, because current methods of refinement over-fit the Bragg diffraction, leading to a component of the disorder that is not based on any experimental data, and could be characterized as a guess. Real-space refinement is less susceptible than other methods, but its application depends on the availability of very accurate experimental phases. A future challenge will be the collection of such data without resort to cryo-techniques, so that a physiologically relevant understanding can be achieved.