Mark DePristo

Supervisor: Prof. Sir Tom Blundell.

School: University of Cambridge.

Highly Commended Talk

Proteins play a fundamental role in all biological processes, and the study of their three-dimensional structures has elucidated the molecular basis of these processes. Proteins are dynamic molecules, exhibiting structural heterogeneity in the form of local anisotropic motion and discrete conformational substates, often of functional importance. In X-ray crystallography, the most successful technique to determine the structure of proteins, the observed diffraction pattern results from the scattering of X-ray by a heterogeneous ensemble of individual molecules. The vast majority of proteins diffract to resolutions where this heterogeneity is difficult to identify and model, and hence is approximated by a single, average conformation with Gaussian, isotropic variance. Here we show that disregarding structural heterogeneity introduces degeneracy into the structure determination process, as many single, isotropic models exist that explain the diffraction data equally well. The large differences among these models implies that the accuracy of crystallographic structures has been widely overestimated. Further, it suggests that analyses that depend on small differences in the relative positions of atoms may be flawed.