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      Conformational Ensemble of hIAPP Dimer: Insight into the Molecular Mechanism by which a Green Tea Extract inhibits hIAPP Aggregation

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          Abstract

          Small oligomers formed early along human islet amyloid polypeptide (hIAPP) aggregation is responsible for the cell death in Type II diabetes. The epigallocatechin gallate (EGCG), a green tea extract, was found to inhibit hIAPP fibrillation. However, the inhibition mechanism and the conformational distribution of the smallest hIAPP oligomer – dimer are mostly unknown. Herein, we performed extensive replica exchange molecular dynamic simulations on hIAPP dimer with and without EGCG molecules. Extended hIAPP dimer conformations, with a collision cross section value similar to that observed by ion mobility-mass spectrometry, were observed in our simulations. Notably, these dimers adopt a three-stranded antiparallel β-sheet and contain the previously reported β-hairpin amyloidogenic precursor. We find that EGCG binding strongly blocks both the inter-peptide hydrophobic and aromatic-stacking interactions responsible for inter-peptide β-sheet formation and intra-peptide interaction crucial for β-hairpin formation, thus abolishes the three-stranded β-sheet structures and leads to the formation of coil-rich conformations. Hydrophobic, aromatic-stacking, cation-π and hydrogen-bonding interactions jointly contribute to the EGCG-induced conformational shift. This study provides, on atomic level, the conformational ensemble of hIAPP dimer and the molecular mechanism by which EGCG inhibits hIAPP aggregation.

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          Most cited references 47

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          Canonical sampling through velocity-rescaling

          We present a new molecular dynamics algorithm for sampling the canonical distribution. In this approach the velocities of all the particles are rescaled by a properly chosen random factor. The algorithm is formally justified and it is shown that, in spite of its stochastic nature, a quantity can still be defined that remains constant during the evolution. In numerical applications this quantity can be used to measure the accuracy of the sampling. We illustrate the properties of this new method on Lennard-Jones and TIP4P water models in the solid and liquid phases. Its performance is excellent and largely independent on the thermostat parameter also with regard to the dynamic properties.
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            Advances in methods and algorithms in a modern quantum chemistry program package.

            Advances in theory and algorithms for electronic structure calculations must be incorporated into program packages to enable them to become routinely used by the broader chemical community. This work reviews advances made over the past five years or so that constitute the major improvements contained in a new release of the Q-Chem quantum chemistry package, together with illustrative timings and applications. Specific developments discussed include fast methods for density functional theory calculations, linear scaling evaluation of energies, NMR chemical shifts and electric properties, fast auxiliary basis function methods for correlated energies and gradients, equation-of-motion coupled cluster methods for ground and excited states, geminal wavefunctions, embedding methods and techniques for exploring potential energy surfaces.
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              Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism.

              The formation of well-ordered fibrillar protein deposits is common to a large group of amyloid-associated disorders. This group consists of several major human diseases such as Alzheimer's disease, Parkinson's disease, prion diseases, and type II diabetes. Currently, there is no approved therapeutic agent directed towards the formation of fibrillar assemblies, which have been recently shown to have a key role in the cytotoxic nature of amyloidogenic proteins. One important approach in the development of therapeutic agents is the use of small molecules that specifically and efficiently inhibit the aggregation process. Several small polyphenol molecules have been demonstrated to remarkably inhibit the formation of fibrillar assemblies in vitro and their associated cytotoxicity. Yet, the inhibition mechanism was mostly attributed to the antioxidative properties of these polyphenol compounds. Based on several observations demonstrating that polyphenols are capable of inhibiting amyloid fibril formation in vitro, regardless of oxidative conditions, and in view of their structural similarities we suggest an additional mechanism of action. This mechanism is assuming structural constraints and specific aromatic interactions, which direct polyphenol inhibitors to the amyloidogenic core. This proposed mechanism is highly relevant for future de novo inhibitors' design as therapeutic agents for the treatment of amyloid-associated diseases.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                13 September 2016
                2016
                : 6
                Affiliations
                [1 ]Key Laboratory for Computational Physical Sciences (MOE), State Key Laboratory of Surface Physics, and Department of Physics, Fudan University , Shanghai 200433, China
                [2 ]College of Physical Science and Technology, Guangxi Normal University , 15 Yucai Road, Guilin, 541004, China
                [3 ]College of Physical Education and Training, Shanghai University of Sport , 399 Changhai Road, Shanghai 200438, China
                Author notes
                Article
                srep33076
                10.1038/srep33076
                5020610
                27620620
                Copyright © 2016, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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