The properties of disordered proteins are thought to depend on intrinsic conformational propensities for polyproline II (PP II) structure. While intrinsic PP II propensities have been measured for the common biological amino acids in short peptides, the ability of these experimentally determined propensities to quantitatively reproduce structural behavior in intrinsically disordered proteins (IDPs) has not been established. Presented here are results from molecular simulations of disordered proteins showing that the hydrodynamic radius (R h) can be predicted from experimental PP II propensities with good agreement, even when charge-based considerations are omitted. The simulations demonstrate that R h and chain propensity for PP II structure are linked via a simple power-law scaling relationship, which was tested using the experimental R h of 22 IDPs covering a wide range of peptide lengths, net charge, and sequence composition. Charge effects on R h were found to be generally weak when compared to PP II effects on R h. Results from this study indicate that the hydrodynamic dimensions of IDPs are evidence of considerable sequence-dependent backbone propensities for PP II structure that qualitatively, if not quantitatively, match conformational propensities measured in peptides.

Intrinsically disordered proteins (IDPs) are often characterized in terms of the hydrodynamic radius, Rh . The Rh of IDPs are known to depend on fractional proline content and net charge, where increased numbers of proline residues and increased net charge cause larger Rh . Though sequence and charge effects on the Rh of IDPs have been studied, the temperature sensitivity has been noted only briefly. Reported here are Rh measurements in the temperature range of 5-75°C for the intrinsically disordered N-terminal region of the p53 protein, p53(1-93). Of note, the Rh of this protein fragment was highly sensitive to temperature, decreasing from 35 Å at 5°C to 26 Å at 75°C. Computer generated simulations of conformationally dynamic and disordered polypeptide chains were performed to provide a hypothesis for the heat-induced compaction of p53(1-93) structure, which was opposite to the heat-induced increase in Rh observed for a model folded protein. The simulations demonstrated that heat caused Rh to trend toward statistical coil values for both proteins, indicating that the effects of heat on p53(1-93) structure could be interpreted as thermal denaturation. The simulation data also predicted that proline content contributed minimally to the native Rh of p53(1-93), which was confirmed by measuring Rh for a substitution variant that had all 22 proline residues changed for glycine.

The authors present a unique case of recurrent stroke, discovered to be secondary to hemorrhagic conversion of microemboli from a mechanical aortic valve despite anticoagulation with Coumadin. The complexity of this case was magnified by the patient’s young age, a mechanical heart valve (MHV), and a need for anticoagulation to maintain MHV patency in a setting of potentially life-threatening intracranial hemorrhage. Anticoagulant and antiplatelet therapy are risk factors for hemorrhagic conversion post-cerebral ischemia; however, the pathophysiology underlying endothelial cell dysfunction causing red blood cell extravasation is an active area of basic and clinical research. The need for randomized clinical trials to aid in the creation of standardized treatment protocol continues to go unmet. Consequently, there is marked variation in therapeutic approaches to treating intracranial hemorrhage in patients with an MHV. Unfortunately, patients with an MHV are considered at high thromboembolic (TE) risk, and these patients are often excluded from clinical trials of acute stroke due to their increased TE potential. The authors feel this case represents an example of endothelial dysfunction secondary to microthrombotic events originating from an MHV, which caused ischemic stroke with hemorrhagic conversion complicated by the need for anticoagulation for an MHV. This case offers a definitive treatment algorithm for a complex clinical dilemma.