Rationalisation of the Differences between APOBEC3G Structures from Crystallography and NMR Studies by Molecular Dynamics Simulations

The human APOBEC3G (A3G) protein is a cellular polynucleotide cytidine deaminase that acts as a host restriction factor of retroviruses, including HIV-1 and various transposable elements. Recently, three NMR and two crystal structures of the catalytic deaminase domain of A3G have been reported, but these are in disagreement over the conformation of a terminal β-strand, β2, as well as the identification of a putative DNA binding site. We here report molecular dynamics simulations with all of the solved A3G catalytic domain structures, taking into account solubility enhancing mutations that were introduced during derivation of three out of the five structures. In the course of these simulations, we observed a general trend towards increased definition of the β2 strand for those structures that have a distorted starting conformation of β2. Solvent density maps around the protein as calculated from MD simulations indicated that this distortion is dependent on preferential hydration of residues within the β2 strand. We also demonstrate that the identification of a pre-defined DNA binding site is prevented by the inherent flexibility of loops that determine access to the deaminase catalytic core. We discuss the implications of our analyses for the as yet unresolved structure of the full-length A3G protein and its biological functions with regard to hypermutation of DNA

Electrocardiogram characteristics prior to in-hospital cardiac arrest

Survival after in-hospital cardiac arrest (I-HCA) remains < 30 %. There is very limited literature exploring the electrocardiogram changes prior to I-HCA. The purpose of the study was to determine demographics and electrocardiographic predictors prior to I-HCA. A retrospective study was conducted among 39 cardiovascular subjects who had cardiopulmonary resuscitation from I-HCA with initial rhythms of pulseless electrical activity (PEA) and asystole. Demographics including medical history, ejection fraction, laboratory values, and medications were examined. Electrocardiogram (ECG) parameters from telemetry were studied to identify changes in heart rate, QRS duration and morphology, and time of occurrence and location of ST segment changes prior to I-HCA. Increased age was significantly associated with failure to survive to discharge (p < 0.05). Significant change was observed in heart rate including a downtrend of heart rate within 15 min prior to I-HCA (p < 0.05). There was a significant difference in heart rate and QRS duration during the last hour prior to I-HCA compared to the previous hours (p < 0.05). Inferior ECG leads showed the most significant changes in QRS morphology and ST segments prior to I-HCA (p < 0.05). Subjects with an initial rhythm of asystole demonstrated significantly greater ECG changes including QRS morphology and ST segment changes compared to the subjects with initial rhythms of PEA (p < 0.05). Diagnostic ECG trends can be identified prior to I-HCA due to PEA and asystole and can be further utilized for training a predictive machine learning model for I-HCA