Peptide-Au Clusters Induced Tumor Cells Apoptosis via Targeting Glutathione Peroxidase-1: The Molecular Dynamics Assisted Experimental Studies

Meiqing Liu,Yawei Zhao,Lina Zhao,Jian He,Qing Yuan,Liang Gao,Xueyun Gao,Peng Zhang

doi:10.1038/s41598-017-00278-6

Abstract

The original motivation of the article is to give a systematic investigation on the protocol of combining computer simulation and accurate synthesis of serial peptide protected gold clusters for potent tumor targeting therapy. Glutathione peroxidase-1 (GPx-1) is a crucial antioxidant selenoenzyme that regulates cellular redox level, thus becomes a potential target in cancer treatment. We firstly utilize molecular dynamic (MD) simulation to rationally design and screen serial peptide-Au cluster compounds with special peptide sequences and precise gold atoms, which can recognize and bind specific domain of GPx-1 with high affinity. The theoretical simulations were further verified by the following peptide-Au clusters synthesis and GPx-1 activity suppression studies in buffer and cells, respectively. Further cytological experiments corroborated that peptide-Au clusters are promising nanoparticles inducing tumor cells apoptosis by suppressing GPx-1 activity and increasing higher cellular reactive oxygen species level to initiate tumor cell apoptosis through intrinsic mitochondrial pathway.

Highlights

The original motivation of the article is to give a systematic investigation on the protocol of combining computer simulation and accurate synthesis of serial peptide protected gold clusters for potent tumor targeting therapy
In the molecular structure design of peptide-Au clusters, we mainly considered the peptide sequences and the definite Au cluster size by checking the surficial electrostatic potential distribution and the concave structure around the Sec of Glutathione peroxidase-1 (GPx-1), respectively (Figure S1)
For the peptide sequence design, we tried to choose highly negatively charged peptide with E (Glu) and D (Asp) to push Au cluster to approach the Sec of GPx-1 by strong electrostatic interaction[24], this because the positive electrostatic potential mainly distributed around the active sites

Summary

Introduction

The original motivation of the article is to give a systematic investigation on the protocol of combining computer simulation and accurate synthesis of serial peptide protected gold clusters for potent tumor targeting therapy. We firstly utilize molecular dynamic (MD) simulation to rationally design and screen serial peptide-Au cluster compounds with special peptide sequences and precise gold atoms, which can recognize and bind specific domain of GPx-1 with high affinity. Nanoparticles could not be described as chemical molecules with precise molecular formula, uniform compositions and exact properties. To explore nanoparticles as efficient inhibitors of therapeutic target, it is highly urgent to rationally design and elaborately synthesize nanoparticles with strict molecular structure, uniform chemical composition and consistent properties. It is a great challenge to achieve peptides with rational composition, sequence and length for precise synthesis of metal clusters with desirable structure, size, charge and targeting ability. With the aid of MD simulations, we attempt to design and synthesize a class of Au clusters with well-defined molecular structure consisting of exact number of peptides and Au atoms. It is anticipated that the peptides would recognize and bind the domain around the Sec site of GPx-1, Au cores would be more prone to interact with active Sec to suppress the enzyme activity with high efficiency

Methods

Results

Conclusion