19 research outputs found

    Exploring the Influence of Carbon Nanoparticles on the Formation of β-Sheet-Rich Oligomers of IAPP<sub>22–28</sub> Peptide by Molecular Dynamics Simulation

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    <div><p>Recent advances in nanotechnologies have led to wide use of nanomaterials in biomedical field. However, nanoparticles are found to interfere with protein misfolding and aggregation associated with many human diseases. It is still a controversial issue whether nanoparticles inhibit or promote protein aggregation. In this study, we used molecular dynamics simulations to explore the effects of three kinds of carbon nanomaterials including graphene, carbon nanotube and C<sub>60</sub> on the aggregation behavior of islet amyloid polypeptide fragment 22–28 (IAPP<sub>22–28</sub>). The diverse behaviors of IAPP<sub>22–28</sub> peptides on the surfaces of carbon nanomaterials were studied. The results suggest these nanomaterials can prevent β-sheet formation in differing degrees and further affect the aggregation of IAPP<sub>22–28</sub>. The <i>π–π</i> stacking and hydrophobic interactions are different in the interactions between peptides and different nanoparticles. The subtle differences in the interaction are due to the difference in surface curvature and area. The results demonstrate the adsorption interaction has competitive advantages over the interactions between peptides. Therefore, the fibrillation of IAPP<sub>22–28</sub> may be inhibited at its early stage by graphene or SWCNT. Our study can not only enhance the understanding about potential effects of nanomaterials to amyloid formation, but also provide valuable information to develop potential β-sheet formation inhibitors against type II diabetes.</p></div

    Schematic diagram of the effects of carbon NPs on the oligomerizations of initial disordered IAPP<sub>22–28</sub> peptides: (A) for four peptides; (B) for eight peptides.

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    <p>Peptides are shown as cartoon, with β-sheet in yellow, β-bridge in lime, and others in white. The NPs are shown as sticks in ice blue. In the two sets, a presents the initial structure of 4-/8-peptide system without NP, and b presents their conformations after 200 ns simulations. In addition, c, d, and e present the corresponding conformations of the peptides interacting with graphene, SWCNT, or C60 after 200 ns simulations, respectively.</p

    Exploring the Molecular Mechanism of Cross-Resistance to HIV‑1 Integrase Strand Transfer Inhibitors by Molecular Dynamics Simulation and Residue Interaction Network Analysis

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    The rapid emergence of cross-resistance to the integrase strand transfer inhibitors (INSTIs) has become a serious problem in the therapy of human immunodeficiency virus type 1 (HIV-1) infection. Understanding the detailed molecular mechanism of INSTIs cross-resistance is therefore critical for the development of new effective therapy against cross-resistance. On the basis of the homology modeling constructed structure of tetrameric HIV-1 intasome, the detailed molecular mechanism of the cross-resistance mutation E138K/Q148K to three important INSTIs (Raltegravir (RAL, FDA approved in 2007), Elvitegravir (EVG, FDA approved in 2012), and Dolutegravir (DTG, phase III clinical trials)) was investigated by using molecular dynamics (MD) simulation and residue interaction network (RIN) analysis. The results from conformation analysis and binding free energy calculation can provide some useful information about the detailed binding mode and cross-resistance mechanism for the three INSTIs to HIV-1 intasome. Binding free energy decomposition analysis revealed that Pro145 residue in the 140s 1oop (Gly140 to Gly149) of the HIV-1 intasome had strong hydrophobic interactions with INSTIs and played an important role in the binding of INSTIs to HIV-1 intasome active site. A systematic comparison and analysis of the RIN proves that the communications between the residues in the resistance mutant is increased when compared with that of the wild-type HIV-1 intasome. Further analysis indicates that residue Pro145 may play an important role and is relevant to the structure rearrangement in HIV-1 intasome active site. In addition, the chelating ability of the oxygen atoms in INSTIs (e.g., RAL and EVG) to Mg<sup>2+</sup> in the active site of the mutated intasome was reduced due to this conformational change and is also responsible for the cross-resistance mechanism. Notably, the cross-resistance mechanism we proposed could give some important information for the future rational design of novel INSTIs overcoming cross-resistance. Furthermore, the combination use of molecular dynamics simulation and residue interaction network analysis can be generally applicable to investigate drug resistance mechanism for other biomolecular systems

    The distribution of different β-sheet size for IAPP<sub>22–28</sub> peptides with or without C<sub>60</sub>.

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    <p>The distribution of different β-sheet size for IAPP<sub>22–28</sub> peptides with or without C<sub>60</sub>.</p