Most enzymes fluctuate between different conformations to accomplish their function, and catalytic or regulatory mechanisms often involve long-range motions. Although X-ray crystallography offers high-resolution views of proteins in different conformations, single or even multiple structures may not provide detailed information on the precise nature of allosteric communication between distant sites. To harvest functional dynamics information from X-ray data, van den Bedem, Fraser and colleagues have now developed a new algorithm called 'contact networks through alternate conformation transitions' (CONTACT). To identify interaction networks, qFit—an algorithm previously developed to extract conformational heterogeneity from X-ray diffraction data—is first used to define possible alternative conformations. CONTACT then uses this information to calculate the van der Waals interactions across all alternative conformations to define those likely to propagate to other residues. As a test of CONTACT's ability to identify contact networks from experimental X-ray data, the authors looked at two enzymes known to undergo pronounced conformational exchanges during catalysis: cyclophilin A (CYPA) and dihydrofolate reductase (DHFR). CONTACT was able to identify multiple plausible transition pathways to known end states of CYPA, results in line with those from recent NMR studies. To study long-range perturbation in DHFR, the authors obtained high-resolution X-ray diffraction data sets of wild-type DHFR at both cryogenic and room temperatures. They identified a contact network that connects the dynamic FG loop, the NADP-binding pocket and the adenosine-binding domain of DHFR. CONTACT predicted that removal of NADP would disrupt coupling between the FG loop and the adenosine-binding domain, and this prediction was experimentally confirmed by NMR analysis of DHFR containing the G121V mutation, located within the FG loop. Similar analyses of another catalytically defective DHFR mutant unexpectedly revealed an expanded contact network resulting in nonproductive motion around the active site and loss of catalytic efficiency. CONTACT should be a useful tool to complement the current arsenal of methods aimed at deciphering protein conformational dynamics. (Nat. Methods 10.1038/nmeth.2592, published online 4 August 2013)