Sensitive detection of structural dynamics using a statistical framework for comparative crystallography

Abstract

Chemical and conformational changes are crucial to protein function and its pharmacological control. X-ray crystallography can reveal these changes in atomic detail, but standard analysis methods, which refine separate datasets, often overlook differences that are subtle or arise in only a subset of molecules. Direct comparison of crystallographic datasets is, in principle, more powerful, but systematic errors (“scales”) often mask changes in the crystallographic observables (“structure factors”). Machine learning algorithms that jointly estimate scales and structure factors can address this limitation. Here, we augment this approach with multivariate, structured priors derived from crystallographic theory, implemented in the variational deep learning framework Careless. Doing so strongly improves the detection of protein dynamics, element-specific anomalous signals, and the binding of drug candidates, offering a robust approach to comparative crystallography and, potentially, to detection of protein dynamics by other structure determination methods.