Catalytic Mechanism of Amyloid-β Peptide Degradation by Insulin Degrading Enzyme: Insights from QM/MM MP2 Calculation

Insulin degrading enzyme (IDE), a metalloprotease that degrades amyloid-β (Aβ) peptides and insulin, is associated with Alzheimer’s disease and diabetes. The mechanism of IDE catalyzed degrading of Aβ peptides, which is of fundamental importance in the design of therapeutic methods for Alzheimer’s disease, has not been fully understood. In this work, combined quantum mechanics and molecular mechanics (QM/MM) style Møller-Plesset second order perturbation theory (MP2) geometry optimization calculations are performed to investigate the catalytic mechanism of the Aβ40 Phe19-Phe20 peptide bond cleavage by human IDE. The analyses using QM/MM MP2 optimization suggest that a neutral water molecule is at the active site of the enzyme-substrate (ES) complex. The water molecule is in hydrogen bonding with the nearby anionic Glu111 of IDE, but not directly bound to the catalytic Zn ion. This is confirmed by QM/MM DFTB3 molecular dynamics simulation. Our studies also reveal that the hydrolysis of the Aβ40 Phe19-Phe20 peptide bond by IDE consists of four key steps. The neutral water is first activated by moving toward and binding to the Zn ion. A gem-diol intermediate is then formed by the activated neutral water molecule attacking the C atom of the Phe19-Phe20 peptide bond. The next is the protonation of the N atom of Phe19-Phe20 peptide bond to form an intermediate with an elongated C-N bond. The final step is the breaking of the Phe19-Phe20 C-N bond. The final step is the rate-determining step with a calculated Gibbs free energy of activation of 17.34 kcal/mol, in good agreement with the experimental value 16.7 kcal/mol. This mechanism provides the basis for the design of biochemical methods to modulate the activity of IDE in humans

Relationship between serum albumin and pulse wave velocity in patients on continuous ambulatory peritoneal dialysis

Li-Tao Cheng1, Li-Jun Tang1,2, Hui-Min Chen1,3, Wen Tang1, Tao Wang11Division of Nephrology, Peking University Third Hospital, Beijing, China; 2Division of Nephrology, Qilu Hospital of Shandong University, Ji’nan, China; 3Division of Cardiology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, ChinaBackground: Hypoalbuminemia is a risk factor for cardiovascular events and mortality in dialysis patients, but the underlying mechanism remains unclear. Meanwhile, increased pulse wave velocity (PWV), the marker of arterial stiffness, has been proved to be an independent predictor of cardiovascular disease. The relationship between serum albumin and PWV in continuous ambulatory peritoneal dialysis patients (CAPD) was studied.Methods: Sixty-two CAPD patients were studied. The average age was 63 ± 12 years and dialysis duration was 23 ± 22 months. Serum albumin, C-reactive protein (CRP), and carotid-femoral PWV were measured.Results: Among these patients, 43.5% were men. The mean serum albumin concentration was 37 ± 4 g/L and PWV was 11.9 ± 2.3 m/s. PWV positively correlated with age (r = 0.35, P < 0.01), diabetes (yes = 1, no = 0; r = 0.292, P < 0.05), systolic blood pressure (SBP; r = 0.493, P < 0.001) and CRP (r = 0.295, P < 0.05), but negatively correlated with serum albumin (r = −0.357, P < 0.01). In multiple regression analysis, SBP (β = 0.615, P < 0.001), age (β = 0.414, P < 0.01), albumin (β = −0.315, P < 0.05) and total cholesterol (β = 0.275, P < 0.05) were independent determinants of PWV. In a non-inflamed subgroup (CRP < 3 mg/L, n = 30), albumin still negatively correlated with PWV (r = −0.66, P < 0.001).Conclusion: Serum albumin inversely correlated with increased PWV in CAPD patients, suggesting that increased arterial stiffness might be the link between hypoalbuminemia and increased cardiovascular mortality in dialysis patients.Keywords: hypoalbuminemia, cardiovascular events, pulse wave velocity, arterial stiffness, peritoneal dialysi

Oriented Graphene Nanoribbons Embedded in Hexagonal Boron Nitride Trenches

Graphene nanoribbons (GNRs) are ultra-narrow strips of graphene that have the potential to be used in high-performance graphene-based semiconductor electronics. However, controlled growth of GNRs on dielectric substrates remains a challenge. Here, we report the successful growth of GNRs directly on hexagonal boron nitride substrates with smooth edges and controllable widths using chemical vapour deposition. The approach is based on a type of template growth that allows for the in-plane epitaxy of mono-layered GNRs in nano-trenches on hexagonal boron nitride with edges following a zigzag direction. The embedded GNR channels show excellent electronic properties, even at room temperature. Such in-plane hetero-integration of GNRs, which is compatible with integrated circuit processing, creates a gapped channel with a width of a few benzene rings, enabling the development of digital integrated circuitry based on GNRs.Comment: 32 pages, 4 figures, Supplementary informatio