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Apart from being the most common mechanism of regulating protein function and transmitting signals throughout the cell, phosphorylation has an ability to induce disorder-to-order transition in an intrinsically disordered protein. In particular, it was shown that folding of the intrinsically disordered protein, eIF4E-binding protein isoform 2 (4E-BP2), can be induced by multisite phosphorylation. Here, the principles that govern the folding of phosphorylated 4E-BP2 (pT37pT46 4E-BP2(18-62)) are investigated by analyzing canonical and replica exchange molecular dynamics trajectories, generated with the coarse-grained united-residue force field, in terms of local and global motions and the time dependence of formation of contacts between Cas of selected pairs of residues. The key residues involved in the folding of the pT37pT46 4E-BP2(18-62) are elucidated by this analysis. The correlations between local and global motions are identified. Moreover, for a better understanding of the physics of the formation of the folded state, the experimental structure of the pT37pT46 4E-BP2(18-62) is analyzed in terms of a kink (heteroclinic standing wave solution) of a generalized discrete nonlinear Schrodinger equation. It is shown that without molecular dynamics simulations the kinks are able to identify not only the phosphorylated sites of protein, the key players in folding, but also the reasons for the weak stability of the pT37pT46 4E-BP2(18-62).

We investigate aspects of topology in protein folding. For this we numerically simulate the temperature driven folding and unfolding of the slipknotted archaeal virus protein AFV3-109. Due to knottiness the (un)folding is a topological process, it engages the entire backbone in a collective fashion. Accordingly we introduce a topological approach to model the process. Our simulations reveal that the (un)folding of AFV3-109 slipknot proceeds through a folding intermediate that has the topology of a trefoil knot. We observe that the final slipknot causes a slight swelling of the folded AFV3-109 structure. We disclose the relative stability of the strands and helices during both the folding and unfolding processes. We confirm results from previous studies that pointed out that it can be very demanding to simulate the formation of knotty self-entanglement, and we explain how the problems are circumvented: The slipknotted AFV3-109 protein is a very slow folder with a topologically demanding pathway, which needs to be properly accounted for in a simulation description. When we either increase the relative stiffness of bending, or when we decrease the speed of ambient cooling, the rate of slipknot formation rapidly increases.

Jonas Hoffmann,1,* Burkhard Haastert,2,* Manuela Brüne,1 Matthias Kaltheuner,3 Alexander Begun,1 Nadja Chernyak,4 Andrea Icks1,4,5 1Institute of Health Services Research and Health Economics, German Diabetes Center, Düsseldorf, Germany; 2mediStatistica, Neuenrade, Germany; 3Specialized Diabetes Practice Leverkusen, Leverkusen, Germany; 4Faculty of Medicine, Centre for Health and Society, Institute of Health Services Research and Health Economics, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany; 5German Center for Diabetes Research, Ingolstädter Neuherberg, Germany *These authors contributed equally to this work Aims: Patients with diabetes are probably often unaware of their comorbidities. We estimated agreement between self-reported comorbidities and administrative data. Methods: In a random sample of 464 diabetes patients, data from a questionnaire asking about the presence of 14 comorbidities closely related to diabetes were individually linked with statutory health insurance data. Results: Specificities were >97%, except cardiac insufficiency (94.5%), eye diseases (93.8%), peripheral arterial disease (92.6%), hypertension (90.9%), and peripheral neuropathy (85.8%). Sensitivities were <60%, except amputation (100%), hypertension (83.1%), and myocardial infarction (67.2%). A few positive predictive values were >90% (hypertension, myocardial infarction, and eye disease), and six were below 70%. Six negative predictive values were >90%, and two <70% (hypertension and eye disease). Total agreement was between 42.7% (eye disease) and 100% (dialysis and amputation). Overall, substantial agreement was observed for three morbidities (kappa 0.61–0.80: hypertension, myocardial infarction, and amputation). Moderate agreement (kappa 0.41–0.60) was estimated for angina pectoris, heart failure, stroke, peripheral neuropathy, and kidney disease. Factors associated with