A designed conformational shift to control protein binding specificity.

In a conformational selection scenario, manipulating the populations of binding-competent states should be expected to affect protein binding. We demonstrate how in silico designed point mutations within the core of ubiquitin, remote from the binding interface, change the binding specificity by shifting the conformational equilibrium of the ground-state ensemble between open and closed substates that have a similar population in the wild-type protein. Binding affinities determined by NMR titration experiments agree with the predictions, thereby showing that, indeed, a shift in the conformational equilibrium enables us to alter ubiquitin's binding specificity and hence its function. Thus, we present a novel route towards designing specific binding by a conformational shift through exploiting the fact that conformational selection depends on the concentration of binding-competent substates.

Improved drinking behaviour improves quality of life: a follow-up in alcohol-dependent subjects 7 years after treatment.

AIM: The present study relates alcohol-dependent patients' Quality of Life (QoL) 7 years after treatment to drinking status as the conventional endpoint of trials. Potential moderating factors such as patients' smoking status, additional healthcare usage and stressful life events were accounted for. METHODS: Seven years after being treated for alcoholism, n = 127 alcohol-dependent patients filled out the Munich List of Quality of Life Dimensions (MLDL), a generic QoL questionnaire and were re-examined in telephone interviews. Patients' drinking and smoking behaviours during the previous year and additional healthcare usage and whether or not they had experienced stressful life events during the whole follow-up period were assessed. RESULTS: Patients reporting abstinence or improved drinking showed significantly higher QoL ratings than patients whose drinking had not improved. Smoking status had no significant effect on QoL. Patients who used additional healthcare during the follow-up period reported lower QoL. The same was true of those who had experienced stressful life events. CONCLUSIONS: Improved drinking after a 7-year follow-up is associated with improved QoL even when considering other factors such as additional healthcare use and stressful life events. We conclude that QoL can be an additional endpoint in treatment trials.