Residue packing in globular and intrinsically disordered proteins.

Intrinsically disordered proteins (IDPs)/regions do not have well-defined secondary and tertiary structures, however, they are functional and it is critical to gain a deep understanding of their residue packing. The shape distributions methodology, which is usually utilized in pattern recognition, clustering, and classification studies in computer science, may be adopted to study the residue packing of the proteins. In this study, shape distributions of the globular proteins and IDPs were obtained to shed light on the residue packing of their structures. The shape feature that was used is the sphericity of tetrahedra obtained by Delaunay Tessellation of points of Cα coordinates. Then the sphericity probability distributions were compared by using Principal Component Analysis. This computational structural study shows that the set of IDPs constitute a more diverse set than the set of globular proteins in terms of the geometrical properties of their network structures.

Analysis of a mathematical model of apoptosis: individual differences and malfunction in programmed cell death.

Apoptosis is an important area of research because of its role in keeping a mature multicellular organism's number of cells constant, hence, ensuring that the organism does not have cell accumulation that may transform into cancer with additional hallmarks. Firstly, we have carried out sensitivity analysis on an existing mathematical mitochondria-dependent apoptosis model to find out which parameters have a role in causing monostable cell survival, which may, in turn, lead to malfunction in apoptosis. We have then generated three base parameter sets that represent healthy cells. These parameter sets were built by changing the sensitive parameters while preserving the bistability. For each base set, we varied the proapoptotic and antiapoptotic production rates, to yield new sets for the cells that have malfunctioning apoptosis. In a hypothetical cell model, we simulated caspase-3 activation by numerically integrating the governing ordinary differential equations of a mitochondria-dependent apoptosis model. These simulations were carried out for four potential treatments, namely: (1) proteasome inhibitor treatment, (2) Bcl-2 inhibitor treatment, (3) IAP inhibitor treatment, (4) Bid-like synthetic peptides treatment. The results suggest that the proteasome inhibitor treatment is the most effective treatment, though it may have severe side effects. For this treatment, the amount of proteasome inhibitor needed for caspase-3 activation may be different for hypothetical cells with a different pro- or anti-apoptotic protein defect. It is also found that caspase-3 can be activated by Bcl-2 inhibitor treatment only in those hypothetical malfunctioning cells with Bax deficiency but not in others. These results are in line with the view that molecular heterogeneity in individuals may be an important factor in determining the individuals' positive or negative responses to treatments.

Inflammatory modulation of hepatocyte apoptosis by nitric oxide: in vivo, in vitro, and in silico studies.

Nitric oxide (NO*) and its reaction products are key players in the physiology and pathophysiology of inflammatory settings such as sepsis and shock. The consequences of the expression of inducible NO* synthase (iNOS, NOS-2) can be either protective or damaging to the liver. We have delineated two distinct hepatoprotective actions of NO*: the stimulation of cyclic guanosine monophosphate and the inhibition of caspases by S-nitrosation. In contrast, iNOS/NO* promotes hepatocyte death under conditions of severe redox stress, such as hemorrhagic shock or ischemia/reperfusion. Redox stress activates an unknown molecular switch that transforms NO*, which is hepatoprotective under resting conditions, into an agent that induces hepatocyte death. We hypothesize that the magnitude of the redox stress is a major determinant for the effects of NO* on cell survival by controlling the chemical fate of NO*. To address this hypothesis, we have carried out studies in relevant in vivo and in vitro settings. Moreover, we have constructed an initial mathematical model of caspase activation and coupled it to a model describing some of the reactions of NO* in hepatocytes. Our studies suggest that modulation of iron, oxygen, and superoxide may dictate whether NO* is hepatoprotective or hepatotoxic.