The abnormal fibrillation of human islet amyloid polypeptide (hIAPP) is associated with development of type II diabetes mellitus (T2DM). (-)-Epigallocatechin gallate (EGCG) can bind amyloid proteins to inhibit the fibrillation of these proteins. However, the mechanic detail of EGCG inhibiting amyloid formation is still unclear at the molecular level. In the present work, we sought to investigate the effect of EGCG on amidated hIAPP (hIAPP-NH ) fibrillation and aggregation by using spectroscopic and microscopic techniques, and also sought to gain insights into the interaction of EGCG and hIAPP by using spectroscopic experiments and quantum chemical calculations. ThT fluorescence, real-time NMR, and TEM studies demonstrated that EGCG inhibits the formation of hIAPP-NH fibrils, while promoting the formation of hIAPP-NH amorphous aggregates. Phenylalanine intrinsic fluorescence and NMR studies of the EGCG/hIAPP complex revealed three important binding sites including the A ring of EGCG, residue Phe23, and residue Ile26. DFT calculations identified the dominant binding structures of EGCG/Phe23 and EGCG/Ile26 complexes, named structure I and structure II, respectively. Our study demonstrates the inhibitory mechanism of EGCG on fibrillation and aggregation of hIAPP-NH in which EGCG interacts with hIAPP-NH through hydrogen bonding and π-π interactions between the A ring and residue Phe23 as well as hydrophobic interactions between the A ring and residue Ile26, which can thus inhibit the interpeptide interaction between hIAPP-NH monomers and finally inhibit fibrillation of hIAPP-NH . This study agrees with and reinforces previous studies and offers an intuitive explanation at both the atomic and molecular levels. Our findings may provide an invaluable reference for the future development of new drugs in the management of diabetes.
The abnormal fibrillation of human islet amyloid polypeptide (hIAPP) has been implicated in the development of type II diabetes. Aluminum is known to trigger the structural transformation of many amyloid proteins and induce the formation of toxic aggregate species. The (−)-epigallocatechin gallate (EGCG) is considered capable of binding both metal ions and amyloid proteins with inhibitory effect on the fibrillation of amyloid proteins. However, the effect of Al(III)/EGCG complex on hIAPP fibrillation is unclear. In the present work, we sought to view insight into the structures and properties of Al(III) and EGCG complex by using spectroscopic experiments and quantum chemical calculations and also investigated the influence of Al(III) and EGCG on hIAPP fibrillation and aggregation as well as their combined interference on this process. Our studies demonstrated that Al(III) could promote fibrillation and aggregation of hIAPP, while EGCG could inhibit the fibrillation of hIAPP and lead to the formation of hIAPP amorphous aggregates instead of the ordered fibrils. Furthermore, we proved that the Al(III)/EGCG complex in molar ratio of 1 : 1 as Al(EGCG)(H2O)2 could inhibit the hIAPP fibrillation more effectively than EGCG alone. The results provide the invaluable reference for the new drug development to treat type II diabetes.
A strategy for the reduction of CO to CO by or catalyzed by metal-free silylboranes has been proposed with the aid of density functional theory (DFT) computations. We showed that one oxygen atom of CO can be abstracted by silylboranes without catalysts or by diboranes in the presence of silylborane catalysts with surprisingly low free-energy barriers so that the reaction can be realized under mild experimental conditions. To achieve this, the reduction mechanism of CO by a hierarchy of silylboranes (R)BSi(R) was systematically investigated. Several rules of thumb were obtained to guide the design of silylboranes with high activity toward CO reduction. After considering many factors, such as side reactions, the stability of the silylboranes, and the solvent effect, two silylboranes, (PFP)BSi(CHF) and MeBSi(CHF), suitable for the reduction of CO under mild experimental conditions were designed. The overall free-energy barriers for the reduction of CO by the two silylboranes are just 26.1-27.0 kcal mol and 28.1-28.9 kcal mol, respectively, at 298.15 K in solution. We further showed that CO can be reduced to CO by diborane MeBBMe using MeBSi(CHF) as the catalyst. The overall free-energy barrier for this catalytic reaction is just 30.6-30.7 kcal mol at 298.15 K in solution.
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