A Peptide-Coated Gold Nanocluster Exhibits Unique Behavior in Protein Activity Inhibition Deyi An, †,‡ Jiguo Su, ‡ Jeffrey K. Weber, § Xueyun Gao, † Ruhong Zhou,* ,§,∥,⊥ and Jingyuan Li* ,† † CAS Key Lab for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Science, Beijing 100049, PR China ‡ College of Science, Yanshan University, Qinhuangdao 066004, PR China § IBM Thomas J. Watson Research Center, Yorktown Heights, New York 10598, United States ∥ Institute of Quantitative Biology and Medicine, SRMP and RAD-X, Soochow University, Suzhou 215123, PR China ⊥ Department of Chemistry, Columbia University, New York, New York 10027, United States * S Supporting Information ABSTRACT: Gold nanoclusters (AuNCs) can be primed for biomedical applications through functionalization with peptide coatings. Often anchored by thiol groups, such peptide coronae not only serve as passivators but can also endow AuNCs with additional bioactive properties. In this work, we use molecular dynamics simulations to study the structure of a tridecapeptide-coated Au 25 cluster and its subsequent inter- actions with the enzyme thioredoxin reductase 1, TrxR1. We find that, in isolation, both the distribution and conformation of the coating peptides fluctuate considerably. When the coated AuNC is placed around TrxR1, however, the motion of the highly charged peptide coating (+5e/peptide) is quickly biased by electrostatic attraction to the protein; the asymmetric coating acts to guide the nanocluster’s diffusion toward the enzyme’s negatively charged active site. After the AuNC comes into contact with TrxR1, its peptide corona spreads over the protein surface to facilitate stable binding with protein. Though individual salt bridge interactions between the tridecapeptides and TrxR1 are transient in nature, the cooperative binding of the peptide-coated AuNC is very stable, overall. Interestingly, the biased corona peptide motion, the spreading and the cooperation between peptide extensions observed in AuNC binding are reminiscent of bacterial stimulus-driven approaching and adhesion mechanisms mediated by cilia. The prevailing AuNC binding mode we characterize also satisfies a notable hydrophobic interaction seen in the association of thioredoxin to TrxR1, providing a possible explanation for the AuNC binding specificity observed in experiments. Our simulations thus suggest this peptide-coated AuNC serves as an adept thioredoxin mimic that extends an array of auxiliary structural components capable of enhancing interactions with the target protein in question. ■ INTRODUCTION Gold nanoparticles, including nanocrystals and nanoclusters, exhibit great potential in drug delivery, diagnostic, and therapeutic applications within a wide range of biomedical fields. 1−3 In order to improve the stability of particulate suspensions, gold nanoparticles are often protected with various synthetic or biologically inspired coatings composed of alkanethiols, DNAs, or peptides. 4−6 Incidentally, such coatings have also been found to modulate the surface properties and reduce the potential cytotoxicity of the underlying gold nanoparticles. 7,8 Peptide-protected gold nanoparticles, in particular, have received growing attention in recent years. 9−13 Peptide coatings can not only bestow remarkable biocompatibility upon nanoparticle systems, but also endow such nanoparticles with biologically specific functionalities. 14−20 For example, gold nanoparticles conjugated with designed peptide sequences can be used to target and bind disease- related proteins of interest, serving as molecular probes for diagnosis as well as therapeutic agents. 15 Furthermore, conjugated peptides can facilitate the transportation of gold nanoparticles through cell membranes. 18 Molecular dynamics (MD) simulations have been previously used to study the properties of coated gold nanoparticles. For example, alkanethiol coatings have been found to favor an asymmetric distribution on their gold nanoparticle substrates that results in anisotropic self-assembly on the mesoscale. 21−23 Furthermore, the adsorption of similar nanoparticles onto lipid bilayers and a resultant disruption of bilayer structure have been characterized. 24,25 The structural 26 and self-assembly 27 proper- ties of DNA-coated gold nanoparticles have also been probed using molecular simulation techniques, as well as the impact of DNA coatings on their interactions with cell membranes. 28 Despite the aforementioned applicability of peptide-coated gold nanoparticles, however, little computational data relevant to these peptide-coated systems exist, to our knowledge. Though Received: January 27, 2015 Article pubs.acs.org/JACS © XXXX American Chemical Society A DOI: 10.1021/jacs.5b00888 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX