The sensing of small molecules poses the challenge of developing devices able to discriminate between compounds that may be structurally very similar. Here, attention has been paid to the use of self-assembled monolayer (SAM)-protected gold nanoparticles since they enable a modular approach to tune single-molecule affinity and selectivity simply by changing functional moieties (i.e., covering ligands), along with multivalent molecular recognition. To date, the discovery of monolayers suitable for a specific molecular target has relied on trial-and-error approaches, with ligand chemistry being the main criterion used to modulate selectivity and sensitivity. By using molecular dynamics, we showcase that either individual molecular characteristics and/or collective features such as ligand flexibility, monolayer organization, ligand local ordering, and interfacial solvent properties can also be exploited conveniently. The knowledge of the molecular mechanisms that drive the recognition of small molecules on SAM-covered nanoparticles will critically expand our ability to manipulate and control such supramolecular systems.

Department of Engineering and Architecture University of Trieste 34127 Trieste Italy

Department of Informatics Jan Evangelista Purkyně University 40096 Ústí nad Labem Czech Republic

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Zhang S.; Geryak R.; Geldmeier J.; Kim S.; Tsukruk V. V. Synthesis, Assembly, and Applications of Hybrid Nanostructures for Biosensing. Chem. Rev. 2017, 117, 12942–13038. 10.1021/acs.chemrev.7b00088. PubMed DOI

Paulovich F. V.; De Oliveira M. C. F.; Oliveira O. N. A Future with Ubiquitous Sensing and Intelligent Systems. ACS Sensors 2018, 3, 1433–1438. 10.1021/acssensors.8b00276. PubMed DOI

Justus K. B.; Hellebrekers T.; Lewis D. D.; Wood A.; Ingham C.; Majidi C.; LeDuc P. R.; Tan C. A Biosensing Soft Robot: Autonomous Parsing of Chemical Signals through Integrated Organic and Inorganic Interfaces. Sci. Robot. 2019, 4, eaax076510.1126/scirobotics.aax0765. PubMed DOI

Fadel T. R.; Farrell D. F.; Friedersdorf L. E.; Griep M. H.; Hoover M. D.; Meador M. A.; Meyyappan M. Toward the Responsible Development and Commercialization of Sensor Nanotechnologies. ACS Sensors 2016, 1, 207–216. 10.1021/acssensors.5b00279. PubMed DOI PMC

Soleymani L.; Li F. Mechanistic Challenges and Advantages of Biosensor Miniaturization into the Nanoscale. ACS Sensors 2017, 2, 458–467. 10.1021/acssensors.7b00069. PubMed DOI

Quesada-González D.; Merkoçi A. Nanomaterial-based Sevices for Point-Of-Care Diagnostic Applications. Chem. Soc. Rev. 2018, 47, 4697–4709. 10.1039/C7CS00837F. PubMed DOI

Zhang A.; Lieber C. M. Nano-Bioelectronics. Chem. Rev. 2016, 116, 215–257. 10.1021/acs.chemrev.5b00608. PubMed DOI PMC

Wongkaew N.; Simsek M.; Griesche C.; Baeumner A. J. Functional Nanomaterials and Nanostructures Enhancing Electrochemical Biosensors and Lab-on-a-Chip Performances: Recent Progress, Applications, and Future Perspective. Chem. Rev. 2019, 119, 120–194. 10.1021/acs.chemrev.8b00172. PubMed DOI

Liu X.; Wang F.; Aizen R.; Yehezkeli O.; Willner I. Graphene Oxide/Nucleic-Acid-Stabilized Silver Nanoclusters: Functional Hybrid Materials for Optical Aptamer Sensing and Multiplexed Analysis of Pathogenic DNAs. J. Am. Chem. Soc. 2013, 135, 11832–11839. 10.1021/ja403485r. PubMed DOI

Howes P. D.; Chandrawati R.; Stevens M. M. Colloidal Nanoparticles as Advanced Biological Sensors. Science 2014, 346, 1247390.10.1126/science.1247390. PubMed DOI

Barnard A.; Posocco P.; Fermeglia M.; Tschiche A.; Calderon M.; Pricl S.; Smith D. K. Double-degradable Responsive Self-assembled Multivalent Arrays – Temporary Nanoscale Recognition between Dendrons and DNA. Org. Biomol. Chem. 2014, 12, 446–455. 10.1039/C3OB42202J. PubMed DOI

Meyyappan M. Carbon Nanotube-Based Chemical Sensors. Small 2016, 12, 2118–2129. 10.1002/smll.201502555. PubMed DOI

Xue T.; Liang W.; Li Y.; Sun Y.; Xiang Y.; Zhang Y.; Dai Z.; Duo Y.; Wu L.; Qi K.; Shivananju B. N.; Zhang L.; Cui X.; Zhang H.; Bao Q. Ultrasensitive Detection of miRNA with an Antimonene-based Surface Plasmon Resonance Sensor. Nat. Commun. 2019, 10, 28.10.1038/s41467-018-07947-8. PubMed DOI PMC

Li Z.; Li H.; Wu Z.; Wang M.; Luo J.; Torun H.; Hu P.; Yang C.; Grundmann M.; Liu X.; Fu Y. Advances in Designs and Mechanisms of Semiconducting Metal Oxide Nanostructures for High-precision Gas Sensors Operated at Room Temperature. Mater. Horiz. 2019, 6, 470–506. 10.1039/C8MH01365A. DOI

Cai R.; Du Y.; Yang D.; Jia G.; Zhu B.; Chen B.; Lyu Y.; Chen K.; Chen D.; Chen W.; Yang L.; Zhao Y.; Chen Z.; Tan W. Free-standing 2D Nanorafts by Assembly of 1D Nanorods for Biomolecule Sensing. Nanoscale 2019, 11, 12169–12176. 10.1039/C9NR02636C. PubMed DOI PMC

Saha K.; Agasti S. S.; Kim C.; Li X.; Rotello V. M. Gold Nanoparticles in Chemical and Biological Sensing. Chem. Rev. 2012, 112, 2739–2779. 10.1021/cr2001178. PubMed DOI PMC

Li B.; Li X.; Dong Y.; Wang B.; Li D.; Shi Y.; Wu Y. Colorimetric Sensor Array Based on Gold Nanoparticles with Diverse Surface Charges for Microorganisms Identification. Anal. Chem. 2017, 89, 10639–10643. 10.1021/acs.analchem.7b02594. PubMed DOI

Cantarutti C.; Bertoncin P.; Posocco P.; Hunashal Y.; Giorgetti S.; Bellotti V.; Fogolari F.; Esposito G. The Interaction of β2-microglobulin with Gold Nanoparticles: Impact of Coating, Charge and Size. J. Mater. Chem. B 2018, 6, 5964–5974. 10.1039/C8TB01129J. PubMed DOI

Yang Y.; Poss G.; Weng Y.; Qi R.; Zheng H.; Nianias N.; Kay E. R.; Guldin S. Probing the Interaction of Nanoparticles with Small Molecules in Real Time via Quartz Crystal Microbalance Monitoring. Nanoscale 2019, 11, 11107–11113. 10.1039/C9NR03162F. PubMed DOI

Prins L. J. Emergence of Complex Chemistry on an Organic Monolayer. Acc. Chem. Res. 2015, 48, 1920–1928. 10.1021/acs.accounts.5b00173. PubMed DOI

Liu X.; Hu Y.; Stellacci F. Mixed-ligand Nanoparticles as Supramolecular Receptors. Small 2011, 7, 1961–1966. 10.1002/smll.201100386. PubMed DOI

Boccalon M.; Bidoggia S.; Romano F.; Gualandi L.; Franchi P.; Lucarini M.; Pengo P.; Pasquato L. Gold Nanoparticles as Drug Carriers: a Contribution to the Quest for Basic Principles for Monolayer Design. J. Mater. Chem. B 2015, 3, 432–439. 10.1039/C4TB01536C. PubMed DOI

Yapar S.; Oikonomou M.; Velders A. H.; Kubik S. Dipeptide Recognition in Water Mediated by Mixed Monolayer Protected Gold Nanoparticles. Chem. Commun. 2015, 51, 14247–14250. 10.1039/C5CC05909G. PubMed DOI

Lucarini M.; Franchi P.; Pedulli G. F.; Gentilini C.; Polizzi S.; Pengo P.; Scrimin P.; Pasquato L. Effect of Core Size on the Partition of Organic Solutes in the Monolayer of Water-Soluble Nanoparticles: An ESR Investigation. J. Am. Chem. Soc. 2005, 127, 16384–16385. 10.1021/ja0560534. PubMed DOI

Sun X.; Liu P.; Mancin F. Sensor Arrays made by Self-organized Nanoreceptors for Detection and Discrimination of Carboxylate Drugs. Analyst 2018, 143, 5754–5763. 10.1039/C8AN01756E. PubMed DOI

Cho E. S.; Kim J.; Tejerina B.; Hermans T. M.; Jiang H.; Nakanishi H.; Yu M.; Patashinski A. Z.; Glotzer S. C.; Stellacci F.; Grzybowski B. A. Ultrasensitive Detection of Toxic Cations through Changes in the Tunnelling Current across Films of Striped Nanoparticles. Nat. Mater. 2012, 11, 978–985. 10.1038/nmat3406. PubMed DOI

Li Y.; Wang Y.; Huang G.; Gao J. Cooperativity Principles in Self-Assembled Nanomedicine. Chem. Rev. 2018, 118, 5359–5391. 10.1021/acs.chemrev.8b00195. PubMed DOI PMC

Bunz U. H. F.; Rotello V. M. Gold Nanoparticle–Fluorophore Complexes: Sensitive and Discerning “Noses” for Biosystems Sensing. Angew. Chem. Int. Ed. 2010, 49, 3268–3279. 10.1002/anie.200906928. PubMed DOI

Pezzato C.; Maiti S.; Chen J. L. Y.; Cazzolaro A.; Gobbo C.; Prins L. J. Monolayer Protected Gold Nanoparticles with Metal-ion Binding Sites: Functional Systems for Chemosensing Applications. Chem. Commun. 2015, 51, 9922–9931. 10.1039/C5CC00814J. PubMed DOI

Ertem E.; Diez-Castellnou M.; Ong Q. K.; Stellacci F. Novel Sensing Strategies Based on Monolayer Protected Gold Nanoparticles for the Detection of Metal Ions and Small Molecules. Chem. Rec. 2018, 18, 819–828. 10.1002/tcr.201700065. PubMed DOI

Perrone B.; Springhetti S.; Ramadori F.; Rastrelli F.; Mancin F. “NMR Chemosensing” Using Monolayer-Protected Nanoparticles as Receptors. J. Am. Chem. Soc. 2013, 135, 11768–11771. 10.1021/ja406688a. PubMed DOI

Riccardi L.; Gabrielli L.; Sun X.; De Biasi F.; Rastrelli F.; Mancin F.; De Vivo M. Nanoparticle-Based Receptors Mimic Protein-Ligand Recognition. Chem 2017, 3, 92–109. 10.1016/j.chempr.2017.05.016. PubMed DOI PMC

Sun X.; Riccardi L.; De Biasi F.; Rastrelli F.; De Vivo M.; Mancin F. Molecular-Dynamics-Simulation-Directed Rational Design of Nanoreceptors with Targeted Affinity. Am. Ethnol. 2019, 58, 7702–7707. 10.1002/anie.201902316. PubMed DOI

Gabrielli L.; Rosa-Gastaldo D.; Salvia M.-V.; Springhetti S.; Rastrelli F.; Mancin F. Detection and Identification of Designer Drugs by Nanoparticle-based NMR Chemosensing. Chem. Sci. 2018, 9, 4777–4784. 10.1039/C8SC01283K. PubMed DOI PMC

Hubble L. J.; Cooper J. S.; Sosa-Pintos A.; Kiiveri H.; Chow E.; Webster M. S.; Wieczorek L.; Raguse B. High-Throughput Fabrication and Screening Improves Gold Nanoparticle Chemiresistor Sensor Performance. ACS Comb. Sci. 2015, 17, 120–129. 10.1021/co500129v. PubMed DOI

Wang J.; Wolf R. M.; Caldwell J. W.; Kollman P. A.; Case D. A. Development and Testing of a General Amber Force Field. J. Comput. Chem. 2004, 25, 1157–1174. 10.1002/jcc.20035. PubMed DOI

Wang J.; Wang W.; Kollman P. A.; Case D. A. Automatic Atom Type and Bond Type Perception in Molecular Mechanical Calculations. J. Mol. Graph. Model. 2006, 25, 247–260. 10.1016/j.jmgm.2005.12.005. PubMed DOI

Vanquelef E.; Simon S.; Marquant G.; Garcia E.; Klimerak G.; Delepine J. C.; Cieplak P.; Dupradeau F.-Y. R.E.D. Server: A Web Service for Deriving RESP and ESP Charges and Building Force Field Libraries for New Molecules and Molecular Fragments. Nucleic Acids Res. 2011, 39, W511–W517. 10.1093/nar/gkr288. PubMed DOI PMC

Heinz H.; Lin T.-J.; Kishore Mishra R.; Emami F. S. Thermodynamically Consistent Force Fields for the Assembly of Inorganic, Organic, and Biological Nanostructures: The INTERFACE Force Field. Langmuir 2013, 29, 1754–1765. 10.1021/la3038846. PubMed DOI

http://openmd.org/download/.

Jensen K. M. Ø.; Juhas P.; Tofanelli M. A.; Heinecke C. L.; Vaughan G.; Ackerson C. J.; Billinge S. J. L. Polymorphism in magic-sized Au144(SR)60 clusters. Nat. Commun. 2016, 7, 11859.10.1038/ncomms11859. PubMed DOI PMC

Chew A. K.; Van Lehn R. C. Effect of Core Morphology on the Structural Asymmetry of Alkanethiol Monolayer-Protected Gold Nanoparticles. J. Phys. Chem. C 2018, 122, 26288–26297. 10.1021/acs.jpcc.8b09323. DOI

Wong O. A.; Heinecke C. L.; Simone A. R.; Whetten R. L.; Ackerson C. J. Ligand Symmetry-Equivalence on Thiolate Protected Gold Nanoclusters Determined by NMR Spectroscopy. Nanoscale 2012, 4, 4099–4102. 10.1039/c2nr30259d. PubMed DOI

Case D.A.; Ben-Shalom I.Y.; Brozell S.R.; Cerutti D.S.; Cheatham T.E.I.; Cruzeiro V.W.D.; Darden T.A.; Duke R.E.; Ghoreishim D.; Gilson M.K.; Gohlke H.; Goetz A.W.; Greene D.; Harris R.; Homeyer N.; Izadi S.; Kovalenko A.; Kurtzman T.; Lee T.S.; LeGrand S.; Li P.; Lin C.; Liu J.; Luchko T.; Luo R.; Mermelstein D.J.; Merz K.M.; Miao Y.; Monard G.; Nguyen C.; Nguyen H.; Omelyan I.; Onufriev A.; Pan F.; Qi R.; Roe D.R.; Roitberg A.; Sagui C.; Schott-Verdugo S.; Shen J.; Simmerling C.L.; Smith J.; Salomon-Ferrer R.; Swails J.; Walker R.C.; Wang J.; Wei H.; Wolf R.M.; Wu X.; Xiao L.; York D.M.; Kollman P. A.. AMBER 2018, University of California, San Francisco.

Berendsen H. J. C.; Postma J. P. M.; van Gunsteren W. F.; DiNola A.; Haak J. R. Molecular Dynamics with Coupling to an External Bath. J. Chem. Phys. 1984, 81, 3684–3690. 10.1063/1.448118. DOI

Darden T.; York D.; Pedersen L. Particle Mesh Ewald: An N·log(N) Method for Ewald Sums in Large Systems. J. Chem. Phys. 1993, 98, 10089–10092. 10.1063/1.464397. DOI

Salomon-Ferrer R.; Case D. A.; Walker R. C. An Overview of the Amber Biomolecular Simulation Package. WIREs Comput. Mol. Sci. 2013, 3, 198–210. 10.1002/wcms.1121. DOI

Salomon-Ferrer R.; Götz A. W.; Poole D.; Le Grand S.; Walker R. C. Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 2. Explicit Solvent Particle Mesh Ewald. J. Chem. Theory 2013, 9, 3878–3888. 10.1021/ct400314y. PubMed DOI

Le Grand S.; Götz A. W.; Walker R. C. SPFP: Speed without compromise—A mixed precision model for GPU accelerated molecular dynamics simulations. Comput. Phys. Commun. 2013, 184, 374–380. 10.1016/j.cpc.2012.09.022. DOI

Wang E.; Sun H.; Wang J.; Wang Z.; Liu H.; Zhang J. Z. H.; Hou T. End-Point Binding Free Energy Calculation with MM/PBSA and MM/GBSA: Strategies and Applications in Drug Design. Chem. Rev. 2019, 119, 9478–9508. 10.1021/acs.chemrev.9b00055. PubMed DOI

Bauer C. A.; Stellacci F.; Perry J. W. Relationship between Structure and Solubility of Thiol-Protected Silver Nanoparticles and Assemblies. Top. Catal. 2008, 47, 32–41. 10.1007/s11244-007-9032-5. DOI

Centrone A.; Penzo E.; Sharma M.; Myerson J. W.; Jackson A. M.; Marzari N.; Stellacci F. The Role of Nanostructure in the Wetting Behavior of Mixed-monolayer-protected Metal Nanoparticles. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 9886–9891. 10.1073/pnas.0803929105. PubMed DOI PMC

Kuna J. J.; Voïtchovsky K.; Singh C.; Jiang H.; Mwenifumbo S.; Ghorai P. K.; Stevens M. M.; Glotzer S. C.; Stellacci F. The Effect of Nanometre-scale Structure on Interfacial Energy. Nat. Mater. 2009, 8, 837–842. 10.1038/nmat2534. PubMed DOI

Ghosh A.; Basak S.; Wunsch B. H.; Kumar R.; Stellacci F. Effect of Composition on the Catalytic Properties of Mixed-ligand-coated Gold Nanoparticles. Angew. Chem. Int. Ed. 2011, 50, 7900–7905. 10.1002/anie.201101821. PubMed DOI

Huang R.; Carney R. P.; Stellacci F.; Lau B. L. T. Colloidal Stability of Self-assembled Monolayer-coated Gold Nanoparticles: The Effects of Surface Compositional and Structural Heterogeneity. Langmuir 2013, 29, 11560–11566. 10.1021/la4020674. PubMed DOI

Huang R.; Carney R. P.; Stellacci F.; Lau B. L. T. Protein-nanoparticle Interactions: The Effects of Surface Compositional and Structural Heterogeneity are Scale Dependent. Nanoscale 2013, 5, 6928–6935. 10.1039/c3nr02117c. PubMed DOI

Nash J. A.; Kwansa A. L.; Peerless J. S.; Kim H. S.; Yingling Y. G. Advances in Molecular Modeling of Nanoparticle–Nucleic Acid Interfaces. Bioconjugate Chem. 2016, 28, 3–10. 10.1021/acs.bioconjchem.6b00534. PubMed DOI

Baron R.; McCammon J. A. Molecular Recognition and Ligand Association. Annu. Rev. Phys. Chem. 2013, 64, 151–175. 10.1146/annurev-physchem-040412-110047. PubMed DOI

Tonelli M.; Boido V.; Colla P. L.; Loddo R.; Posocco P.; Paneni M. S.; Fermeglia M.; Pricl S. Pharmacophore Modeling, Resistant Mutant Isolation, Docking, and MM-PBSA analysis: Combined Experimental/Computer-Assisted Approaches to Identify New Inhibitors of the Bovine Viral Diarrhea Virus (BVDV). Bioorg. Med. Chem. 2010, 18, 2304–2316. 10.1016/j.bmc.2010.01.058. PubMed DOI

Bromfield S. M.; Posocco P.; Fermeglia M.; Pricl S.; Rodríguez-López J.; Smith D. K. A Simple New Competition Assay for Heparin Binding in Serum Applied to Multivalent PAMAM Dendrimers. Chem. Commun. 2013, 49, 4830–4832. 10.1039/c3cc41251b. PubMed DOI

Bromfield S. M.; Posocco P.; Chan C. W.; Calderon M.; Guimond S. E.; Turnbull J. E.; Pricl S.; Smith D. K. Nanoscale Self-assembled Multivalent (SAMul) Heparin Binders in Highly Competitive, Biologically Relevant, Aqueous Media. Chem. Sci. 2014, 5, 1484–1492. 10.1039/c4sc00298a. DOI

Kong X.; Sun H.; Pan P.; Zhu F.; Chang S.; Xu L.; Li Y.; Hou T. Importance of Protein Flexibility in Molecular Recognition: A Case Study on Type-I1/2 Inhibitors of ALK. Phys. Chem. Chem. Phys. 2018, 20, 4851–4863. 10.1039/C7CP08241J. PubMed DOI

Chen C.; Posocco P.; Liu X.; Cheng Q.; Laurini E.; Zhou J.; Liu C.; Wang Y.; Tang J.; Col V. D.; Yu T.; Giorgio S.; Fermeglia M.; Qu F.; Liang Z.; Rossi J. J.; Liu M.; Rocchi P.; Pricl S.; Peng L. Mastering Dendrimer Self-Assembly for Efficient siRNA Delivery: From Conceptual Design to In Vivo Efficient Gene Silencing. Small 2016, 12, 3667–3676. 10.1002/smll.201503866. PubMed DOI PMC

Laurini E.; Harel D.; Marson D.; Schepmann D.; Schmidt T. J.; Pricl S.; Wünsch B. Identification, pharmacological evaluation and binding mode analysis of novel chromene and chromane based σ1 receptor ligands. Eur. J. Med. Chem. 2014, 83, 526–533. 10.1016/j.ejmech.2014.06.054. PubMed DOI

Laurini E.; Marson D.; Posocco P.; Fermeglia M.; Pricl S. Structure and Binding Thermodynamics of Viologen-phosphorous Dendrimers to Human Serum Albumin: A Combined Computational/Experimental Investigation. Fluid Phase Equilib. 2016, 422, 18–31. 10.1016/j.fluid.2016.02.014. DOI

Fox J. M.; Zhao M.; Fink M. J.; Kang K.; Whitesides G. M. The Molecular Origin of Enthalpy/Entropy Compensation in Biomolecular Recognition. Annu. Rev. Biophys. 2018, 47, 223–250. 10.1146/annurev-biophys-070816-033743. PubMed DOI

Giri A. K.; Spohr E. Influence of Chain Length and Branching on the Structure of Functionalized Gold Nanoparticles. J. Phys. Chem. C 2018, 122, 26739–26747. 10.1021/acs.jpcc.8b08590. DOI

Yeon H.; Wang C.; Van Lehn R. C.; Abbott N. L. Influence of Order within Nonpolar Monolayers on Hydrophobic Interactions. Langmuir 2017, 33, 4628–4637. 10.1021/acs.langmuir.7b00226. PubMed DOI

Dallin B. C.; Yeon H.; Ostwalt A. R.; Abbott N. L.; Van Lehn R. C. Molecular Order Affects Interfacial Water Structure and Temperature-Dependent Hydrophobic Interactions between Nonpolar Self-Assembled Monolayers. Langmuir 2019, 35, 2078–2088. 10.1021/acs.langmuir.8b03287. PubMed DOI

Dallin B. C.; Van Lehn R. C. Spatially Heterogeneous Water Properties at Disordered Surfaces Decrease the Hydrophobicity of Nonpolar Self-Assembled Monolayers. J. Phys. Chem. Lett. 2019, 10, 3991–3997. 10.1021/acs.jpclett.9b01707. PubMed DOI

Spotting Local Environments in Self-Assembled Monolayer-Protected Gold Nanoparticles