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Combining conformational sampling and selection to identify the binding mode of zinc-bound amyloid peptides with bifunctional molecules

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Abstract

The pathogenesis of Alzheimer’s disease (AD) has been suggested to be related with the aggregation of amyloid β (Aβ) peptides. Metal ions (e.g. Cu, Fe, and Zn) are supposed to induce the aggregation of Aβ. Recent development of bifunctional molecules that are capable of interacting with Aβ and chelating biometal ions provides promising therapeutics to AD. However, the molecular mechanism for how Aβ, metal ions, and bifunctional molecules interact with each other is still elusive. In this study, the binding mode of Zn2+-bound Aβ with bifunctional molecules was investigated by the combination of conformational sampling of full-length Aβ peptides using replica exchange molecular dynamics simulations (REMD) and conformational selection using molecular docking and classical MD simulations. We demonstrate that Zn2+-bound Aβ(1–40) and Aβ(1–42) exhibit different conformational ensemble. Both Aβ peptides can adopt various conformations to recognize typical bifunctional molecules with different binding affinities. The bifunctional molecules exhibit their dual functions by first preferentially interfering with hydrophobic residues 17–21 and/or 30–35 of Zn2+-bound Aβ. Additional interactions with residues surrounding Zn2+ could possibly disrupt interactions between Zn2+ and Aβ, which then facilitate these small molecules to chelate Zn2+. The binding free energy calculations further demonstrate that the association of Aβ with bifunctional molecules is driven by enthalpy. Our results provide a feasible approach to understand the recognition mechanism of disordered proteins with small molecules, which could be helpful to the design of novel AD drugs.

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Abbreviations

AD:

Alzheimer’s disease

Aβ:

Amyloid-β

REMD:

Replica exchange molecular dynamics

HBX:

2-(2-Hydroxylphenyl)benzoxazole

MPY′:

4-(5-Hydoxylimidazo[1,2-a]pyridin-2-yl)-N,N-dimethylaniline

L2B:

N1,N1-dimethyl-N4-(pyridin-2-ylmethyl)benzene-1,4-diamine

EDTA:

Ethylenediaminetetraacetic acid

CQ:

Clioquinol, 5-chloro-7-iodo-8-hydroxyquinoline

PBT2:

8-Hydroxyquinoline derivative

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Acknowledgments

We are grateful to Dr. Orkid Coskuner-Weber (The University of Texas at San Antonio, USA) for critical comments of this research. Computations were performed on the clusters at the High-Performance Computing Center of Dalian University of Technology. This work is supported by the Major State Basic Research Development Program (Grant No. 200900376). Dr. Xu and Dr. Bao thanks financial support from the Fundamental Research Funds for the Central Universities (grant No. DUT12LK38 and DUT11SM01).

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  1. School of Chemistry, Dalian University of Technology, Dalian, 116024, China

    Liang Xu, Ke Gao & Chunyu Bao

  2. Department of Engineering Mechanics, State Key Laboratory of Structural Analyses for Industrial Equipment, Dalian University of Technology, Dalian, 116023, China

    Xicheng Wang

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  1. Liang Xu
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Correspondence to Liang Xu.

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10822_2012_9588_MOESM1_ESM.doc

Supplementary Material The computational details of RESP charges for the model structures, as well as figures mentioned in the main text are provided in the Supplementary Material. (DOC 10712 kb)

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Xu, L., Gao, K., Bao, C. et al. Combining conformational sampling and selection to identify the binding mode of zinc-bound amyloid peptides with bifunctional molecules. J Comput Aided Mol Des 26, 963–976 (2012). https://doi.org/10.1007/s10822-012-9588-4

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