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WO1999005509A1 - Detection et investigation de molecules biologiques par spectroscopie a infrarouge et transformees de fourier - Google Patents

Detection et investigation de molecules biologiques par spectroscopie a infrarouge et transformees de fourier Download PDF

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Publication number
WO1999005509A1
WO1999005509A1 PCT/IB1997/000920 IB9700920W WO9905509A1 WO 1999005509 A1 WO1999005509 A1 WO 1999005509A1 IB 9700920 W IB9700920 W IB 9700920W WO 9905509 A1 WO9905509 A1 WO 9905509A1
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Prior art keywords
molecules
self
biological
metal
gold
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PCT/IB1997/000920
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English (en)
Inventor
Horst Vogel
Thomas Keller
Martha Liley
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Ecole Polytechnique Federale De Lausanne
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Filing date
Publication date
Application filed by Ecole Polytechnique Federale De Lausanne filed Critical Ecole Polytechnique Federale De Lausanne
Priority to PCT/IB1997/000920 priority Critical patent/WO1999005509A1/fr
Priority to EP97929474A priority patent/EP1002226A1/fr
Priority to AU33565/97A priority patent/AU3356597A/en
Publication of WO1999005509A1 publication Critical patent/WO1999005509A1/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/55—Specular reflectivity
    • G01N21/552—Attenuated total reflection

Definitions

  • the invention concerns methods and devices for the detection and investigation of biological molecules at or in self-assembled monolayers on metal sur- faces using infrared spectroscopy in the attenuated total internal reflection configuration.
  • SAMs self-assembled monolayers
  • SAMs are monomolecular layers formed on solid surfaces by the immersion of a substrate into a solution of the appropriate surfactant.
  • the surfactant contains a functional group which reacts specifically with the sur- face: chemisorption of the surfactant to the surface produces a highly ordered densely packed monolayer.
  • the high stability and reproducibility of SAMs, the wide range of surface functionalities that can be produced, and their ease of manufacture makes them potentially applicable in many fields including corrosion prevention, wear protection, adhesion, electrode surfaces, photoactive materials, bioco patibility, biosensing, etc.
  • Various surfactant/substrate pairs have been used for the formation of self-assembled monolayers.
  • SAMs are those of sulfur-containing molecules on metals (e.g. Au, Ag, Cu, Pt) .
  • SAMs offer a unique opportunity in sur- face science since they allow the easy creation of well- defined surfaces whose properties can be systematically varied.
  • the most com- monly used analytical techniques for metal surfaces in aqueous media are: surface plasmon resonance (which measures mass loading of the surface) ; scanning probe micro- scopies; electrochemical techniques such as ac impedance spectroscopy and cyclic voltammetry; neutron scattering. These techniques have very limited access to structural information about chemical and biological species at the surface - molecular packing, orientation, chemical structure - especially if time-resolved information is required.
  • FTIR Fourier transform infra-red
  • infrared spectroscopy for the investigation of monolayer and multilayer organic samples in air or vacuum is well-developed both for oxide surfaces (attenuated total internal reflection configuration, ATR) and for metal surfaces (grazing incident angle configuration) .
  • ATR attenuated total internal reflection configuration
  • metal surfaces grazing incident angle configuration
  • ultra-thin organic films at metal/water interfaces remains very difficult. This is due to the very high absorption of infrared light by water, which renders the grazing incident angle configuration unworkable.
  • Most studies of metal/ water interfaces use a odi- fied grazing incident angle configuration with the thinnest possible water cell (l-10 ⁇ m thickness, formed by clamping the metal surface against the cell window) , and a much higher angle of incidence (Faguy, P. W.; Marink- ovic, N.
  • the present invention provides a method to study biological molecules at or in self-assembled mono- layers on metal surfaces, particularly gold surfaces, in aqueous environments by using attenuated total internal reflection (ATR) infra-red (IR) spectroscopy, preferably, because of its improved sensitivity, Fourier transform infra-red (FTIR) spectroscopy.
  • ATR attenuated total internal reflection
  • IR infra-red
  • FTIR Fourier transform infra-red
  • the inventive method allows the study of biological molecules which form a self-assembled monolayer (SAM) and/or biological molecules which are immobilised on a SAM and/or biological molecules which react with a SAM, their interactions with surfaces such as cells or cell fragments or their interactions with other biological molecules, with ions or with other water-soluble molecules.
  • SAM self-assembled monolayer
  • Such ions and water-soluble molecules are understood as also comprising complexes.
  • the relative transparency of the thin metal films, e.g. gold films, in the infra-red is exploited: internal reflection of the infra-red beam at the interface between the ATR element and the metal produces an evanescent field which pene- trates through the metal film and into the aqueous phase on the other side.
  • Figure 1 is a schematic cross-section of an inventive device
  • Figure 2 is a comparison of spectra of a N ⁇ ,N ⁇ -bis (carboxymethyl) -N TO - (11-mercaptoundecanoyl- glycyl-glycyl-glycyl) -L-lysine (CTA) layer and N ⁇ ,N ⁇ - bis (carboxymethyl) -L-lysine (lysine-NTA) in solution without (part A) and with (part B) ion (Ni ⁇ ) complexa- tion,
  • Figure 3 is a difference spectrum between a nickel-charged CTA SAM with Fab fragment and the same SAM without Fab
  • Figure 4 shows the adsorption kinetic of the
  • the present invention concerns a method to study biological molecules or their interaction or com- plexation or reaction with ions and/or biological molecules and/or biological components and/or other molecules at or in self-assembled monolayers (SAMs) on gold or other metal surfaces in aqueous environments by using attenuated total internal reflection (ATR) infra-red (IR) spectroscopy, particularly Fourier transform infra-red (FTIR) spectroscopy.
  • ATR total internal reflection
  • IR infra-red
  • FTIR Fourier transform infra-red
  • This technique is based on the use of thin films (about 1 to about 30 nm) of metals, par- ticularly gold, deposited on ATR elements.
  • metal films Preferably such metal films have a thickness of 3 to 15 nm, particularly 5 to 10 nm.
  • Metals other than gold are e.g. Ag, Cu, Pt, Au/Pt, alloys, particularly gold comprising alloys, multilayers, particularly bilayers of metals such as gold on chromium or titanium.
  • the deposition of e.g. gold on a very thin layer of another metal is suitable for the formulation of thin gold films with smooth surfaces.
  • the self-assembled monolayer is prepared by contacting a first solution comprising a self- assembled-monolayer-forming molecule to at least one metal-coated surface of said attenuated total internal reflection (ATR) element.
  • Said SAM may be further reacted with other molecules to give new surface functional groups or to form one or more additional layer (s) on the metal surface, thus enabling the study of said new surface functional groups or said one or more additional layer (s) at the SAM, their interaction or complexation or reaction with ions and/or biological molecules and/or biological components and/or other molecules in solution at the SAM.
  • the first solution of the self-assembled- monolayer-forming molecule can be removed and a second or further solution comprising a metal ion and/or a biological molecule and/or other molecules can be applied to the monolayer in order to study the interactions of self- assembled monolayers with ions and/or biological molecules and/or other molecules, and/or cells or cell fragments, with at least those solutions being in contact with biological molecules and/or components being aqueous solutions.
  • the SAM comprises itself biological molecules, then the molecules of the second or further solution usually of course will be different from those of the SAM.
  • the present invention also concerns a method to provide such information time-resolved for the study of the kinetics of such processes, particularly for stud- ies with a good time resolution, preferably a time resolution on the seconds scale.
  • the method of the present invention is e.g. a suitable method for a screening for effector compounds and for the evaluation of the activity of pharmacological agents as agonists or antagonists for biosensitive receptor proteins.
  • screening becomes more and more important for the detection of substances that are e.g. active modulators of membrane proteins.
  • the inventive method provides a sensitive method for an efficient drug screening of e.g. such modulators with high throughput.
  • the study of molecules or components of interest may include their identification or quantification, or their functional characterization or characterization of their conformation, orientation or ordering us- ing or based on their specific infra-red spectra.
  • the present invention furthermore concerns a solid device as e.g. the one shown in Figure 1.
  • Said solid device (ATR element) 1 is transparent in the infrared and one or more surfaces thereof are coated with a thin film 2 of gold or of another suitable metal or alloy or mixture of metals as described above.
  • the coating with a metal layer is such as to enable generation of an evanescent field 4 at the interface water/metal, said metal layer 2 being transparent to an infra-red beam 5.
  • Said thin metal layer 2 for the use in the inventive method must be provided with a SAM.
  • ATR elements are made from a material chosen from the following group: germanium, silicon, ZnSe, ZnS, AMTIR (an amorphous glass of germanium, selenium and arsenic) .
  • the thin metal layer has a thickness from about 1 to about 30 nm, preferably 3 to 15 nm, particularly 5 to 10 nm.
  • the self-assembled monolayer is formed of molecules containing metal-surface reactive groups, preferably chosen from the following groups: thiols, di- sulfides, thiophenes, phosphines and isonitriles.
  • Such an inventive device can be produced by coating an attenuated total internal reflection (ATR) element with a thin metal layer on at least one face. Such coating is performed by means of known methods for the preparation of thin metallic films, e.g. physical vapour deposition (PVD) .
  • PVD physical vapour deposition
  • said at least one metal coated face of the inventive device (ATR element) is then pressed against a partial cell (said partial cell provides the further cell walls) thus that a water-tight cell 3 is generated of which at least one face or part of one of the faces is formed by a metal layer of the ATR element.
  • Such a cell consisting of an inventive device and a partial cell thus combined that they form a cell 3 with one face being at least partially formed by the ATR metal coating is also part of the present invention.
  • Such a cell can have varying volumes, preferably volumes easily allowing the replacement of the solution comprised therein.
  • the metal- coated surface or surfaces are first brought into contact with a solution (not necessarily an aqueous solution) comprising molecules suitable to form a self-assembled monolayer.
  • a solution not necessarily an aqueous solution
  • molecules may be biological molecules to be studied or an other molecule the interaction of which with biological molecules shall be studied or which shall be used for the immobilisation of biological molecules on the surface.
  • the first solution is removed and replaced by another solution comprising the interacting biological molecule and/or biological component and/or ion and/or other molecules present in the solution.
  • the self-assembled monolayer and/or the interacting molecule are biological molecules or biological components such as cells, cell fragments (e.g. parts of the cell membrane), at least the second and/or further solutions are aqueous solutions.
  • the properties e.g.
  • hydrophilicity, protein binding properties, ion complexation abilities) of the metal coated surface or surfaces are defined by the self- assembled monolayer which is formed on the metal surface: the choice of the appropriate molecules or mixture of molecules for the SAM allows control of these surface properties.
  • the SAM may be formed of biomolecules (e.g. peptides, DNA, RNA, sugars) or may be formed of other suitable molecules (e.g. al- kanethiols, hydroxyalkanethiols, carboxyalkanethiols) .
  • the SAM may be formed on the metal-coated surface either before or after bringing it into contact with an aqueous medium.
  • the inventive method generally allows the investigation of biological molecules, for example, proteins (such as receptors, enzymes, antibodies, transmem- brane proteins) , DNA, RNA, polysaccharides, lipids, natural or synthetic peptides.
  • biological molecules for example, proteins (such as receptors, enzymes, antibodies, transmem- brane proteins) , DNA, RNA, polysaccharides, lipids, natural or synthetic peptides.
  • Biological components may also be investigated: for example whole cells or cell fragments .
  • An infrared beam incident on the device passes inside it where it is internally reflected at one or more of the metal-coated surfaces before exiting the device for spectroscopic analysis.
  • the thickness of the metal coating is chosen so that internal reflection of the infrared beam in the device produces an evanescent field at the SAM at the interface between metal and aqueous medium. It has been found that the interactions of said evanescent field with the biomolecules present at or in the SAM are observable in the spectrum of the infrared beam which exits the device and thus allows their inves- tigation and study.
  • the optimal film e.g. gold film
  • the optimal film must be thin enough that the evanescent field at the metal, particularly gold, water interface has a high intensity, while the reflectivity of the metal/ATR element interface must also be relatively high.
  • This optimal film thickness is a function of the optical parame- ters chosen e.g. detector sensitivity, number of reflections at the metal coated surface.
  • the film must adhere well to the ATR element and form a continuous smooth metal layer covering the entire surface of the ATR element. Scanning electron microscopy and conductivity measurements of gold layers indicate, however, that even films with defects such as holes comprising as much as about 15-20 % of the surface are already suitable for some investigations.
  • Figure 1 suitable for the inventive method can be produced and used as follows.
  • a germanium attenuated total internal reflection (ATR) element 1 is coated with a thin layer 2 (approx. 3nm) of gold on one face. This face is pressed against a cell to form a water-tight seal.
  • the cell may be of any inert material, however, the material preferably is polytetrafluoroethylene (herein further on referred to under its generally used trade mark name Tef- Ion®) .
  • Tef- Ion® polytetrafluoroethylene
  • the gold film is used as a substrate for self- assembly of e.g. thiol monolayers.
  • Evanescent waves 4 are produced upon application of an infra-red beam 5.
  • the cell is filled with aqueous solution 6.
  • heavy water (D2O) media may be used. Such a device (with D2O medium) is used in the following examples.
  • SAM can be used more than once, but that the SAM on either the metal surface or the precursor-treated metal surface can be replaced if need be and even the metal layer can be removed by well established chemical methods without affecting the ATR-element and a new metal layer can be applied to the ATR-element, thus allowing its multiple use. Since the present method is particularly suitable for investigations with small amounts of interesting material, it is of course much preferred to use the more sensitive Fourier transform infra-red spectros- copy than usual dispersive IR spectroscopy.
  • Example 1 Investigation and characterisation of binding reactions of a peptide self-assembled monolayer with such a device.
  • Step 1 Preparation of the device
  • a device similar to that shown in Figure 1 and described above is prepared by thermal evaporation in vacuum of less than 10 ⁇ 5 m ar of a thin layer of gold onto one surface of a germanium ATR element at room tem- perature (60x10x4mm with an internal angle of incidence of 45°) .
  • the ATR element was prepared for this treatment by silanisation with 3- (mercaptopropyl) trimethoxysilane, which is a suitable treatment for the formation of thin gold films with smooth surfaces.
  • Step 2 Formation of a SAM of a peptide on the device
  • CTA chelator thioalkane
  • Lysine-NTA N ⁇ , N ⁇ -bis (carboxymethyl) -L-lysine
  • Step 3 Analysis of the peptide SAM
  • Spectra of the CTA SAM were obtained by comparing spectra of the device after treatment with CTA with spectra of the device before. Spectra of CTA monolayers and the bare gold surface were recorded in deuter- ated buffer (20mM sodium phosphate, 250mM NaCl, pD 7.5) . These spectra are shown in Figure 2, Part A and compared with transmission spectra of a thin film of aqueous solu- tion ( ⁇ 60 ⁇ m) of the comparison molecule lysine NTA taken in the same buffer.
  • the lysine-NTA spectrum has two major peaks at 1625cm -1 and at 1402cm -1 . These are assigned to the carboxylate asymmetric (v a sym) anci symmetric stretch ( sym) respectively.
  • the peak at 1730cm-l is assigned to a minor component of protonated carboxylic acid groups.
  • the spectrum of the CTA SAM at the gold surface retains the two major peaks: the peak at 1624cm -1 is attributed to the carboxylate asymmetric stretch and the amide I' band of the 4 peptide bonds in the CTA spacer; the peak at 1403cm -1 is attributed to the carboxylate symmetric stretch; while the new peak at around 1467cm -1 is attributed to the amide II' bands of the (deuterated) peptide bonds with a contribution from the ⁇ (CH2) modes.
  • Step 4 Investigations of the ion complexa- tion reactions of the peptide SAM
  • the ion complexation reactions of the peptide SAM were studied by incubating the CTA monolayer with a solution containing Ni ⁇ ions in heavy water (50mM i2S04) for one minute. After washing, spectra were re- corded in deuterated buffer (20mM sodium phosphate, 250mM NaCl, pD 7.5) . The spectra of the CTA monolayer were compared with transmission spectra of lysine-NTA recorded in 20mM sodium phosphate, 250mM NaCl, 20mM NiSOj, pD 7.5 as shown in Figure 2, Part B.
  • Step 1 Preparation of the device
  • a device was prepared as described in example 1, a self-assembled monolayer of CTA was formed on the gold surface, and the CTA SAM was incubated with nickel ions and washed.
  • Step 2 Binding of Fab fragment to the device
  • the anti-lysozyme Fab fragment Dl .3 bearing a hexahistidine extension at the C-terminus of the heavy chain was equilibrated in deuterated buffer for a period of several days.
  • the absence of an amide II peak in the spectral region 1510-1580cm -1 was indicative of quasi- complete exchange of amide protons for deuterons.
  • the metal-coated surface of the device, with the nickel-charged CTA SAM was incubated with a l ⁇ M solution of the Fab in deuterated buffer (20mM sodium phosphate, 250mM NaCl, pD 7.5) for 30 minutes. After washing with buffer, infrared spectra were recorded.
  • the spectrum shown in Figure 3 is the difference spectrum between a nickel-charged CTA SAM with Fab and the same SAM without Fab.
  • the frequency range 1700-1600cm-l is shown as this is the range in which the amide I peak is found.
  • the amide I peak is characteristic of the secondary structure of the protein.
  • Step 3 Desorption of Fab fragment from the device After adsorption of the Fab fragment, the device was incubated with a deuterated solution of imida- zole (250mM imidazole in 20mM sodium phosphate, 250mM NaCl, pD 9.5) for 10 minutes and washed with buffer. New spectra of the Fab revealed that 80-90% of the protein was desorbed from the gold surface.
  • imida- zole 250mM imidazole in 20mM sodium phosphate, 250mM NaCl, pD 9.5
  • Example 3 Time resolved measurements of the binding reactions of the Fab to the device.
  • Step 1 Preparation of the device
  • the device was prepared with a nickel-charged CTA SAM as described in examples 1 and 2.
  • Step 2 Measurement of the adsorption of the Fab
  • the device was incubated with a deuterated solution of Fab fragment as described in example 2. Before addition of the solution of Fab, initial spectra of the device surface were measured. Numerous spectra were measured at regular intervals during the entire adsorption process until it had finished. The intensities of the amide I peak for the different spectra were measured and the integrated intensity plotted against time as shown in Figure 4 to obtain the adsorption kinetic for the Fab fragment .

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Abstract

L'invention porte sur une méthode et un appareil visant à étudier des molécules biologiques ou des composants biologiques au niveau ou dans des monocouches auto-assemblées (SAMs) sur des surfaces métalliques (2) telles que de l'or dans des environnements aqueux (6) par spectroscopie à infrarouge et transformées de Fourier à réflexion interne totale atténuée. Cette méthode peut être utilisée, par exemple, dans le dépistage de substances efficaces appropriées pour être utilisées comme agonistes ou antagonistes ou, dans le cas d'une résolution temporelle, dans l'étude de la cinétique des interactions des processus d'adsorption et de désorption des molécules biologiques, par exemple, ou dans le développement de matières et de surfaces destinées à être utilisées dans des applications biologiques ou médicales.
PCT/IB1997/000920 1997-07-24 1997-07-24 Detection et investigation de molecules biologiques par spectroscopie a infrarouge et transformees de fourier WO1999005509A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PCT/IB1997/000920 WO1999005509A1 (fr) 1997-07-24 1997-07-24 Detection et investigation de molecules biologiques par spectroscopie a infrarouge et transformees de fourier
EP97929474A EP1002226A1 (fr) 1997-07-24 1997-07-24 Detection et investigation de molecules biologiques par spectroscopie a infrarouge et transformees de fourier
AU33565/97A AU3356597A (en) 1997-07-24 1997-07-24 Detection and investigation of biological molecules by fourier transform nfra-red spectroscopy

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PCT/IB1997/000920 WO1999005509A1 (fr) 1997-07-24 1997-07-24 Detection et investigation de molecules biologiques par spectroscopie a infrarouge et transformees de fourier

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Cited By (16)

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WO2001086022A1 (fr) * 2000-05-09 2001-11-15 Pace University Procede de preparation de feuilles metalliques fines et de structures constituees fines couches de metal organique
WO2002056018A1 (fr) * 2001-01-16 2002-07-18 Universite Catholique De Louvain Modification chimique de surfaces d'elements optiques
WO2002082061A1 (fr) * 2001-04-05 2002-10-17 Austria Wirtschaftsservice Gesellschaft mit beschränkter Haftung Procede de surveillance de processus biotechnologiques
WO2002006407A3 (fr) * 2000-07-17 2003-02-13 Harvard College Surfaces resistant a l'adsorption d'especes biologiques
WO2003085422A2 (fr) * 2001-09-04 2003-10-16 North Carolina State University Appareil de microscopie infrarouge a transformee de fourier, a passe unique et reflexion totale attenuee, et procede d'identification de structure secondaire, de charge de surface et d'affinite de proteine
DE10214781A1 (de) * 2002-04-03 2003-10-30 Univ Jw Goethe Frankfurt Main FT-IR-Meßvorrichtung, insbesondere für die Spektrometrie wässriger Systeme
DE10254389B3 (de) * 2002-11-21 2004-06-24 Kist-Europe Forschungsgesellschaft Mbh Verfahren zur Quantifizierung des Beschichtungsgrades selbstorganisierender Thiolgruppen-haltiger Monolayer auf einem Goldsubstrat
US7033542B2 (en) 2002-02-14 2006-04-25 Archibald William B High throughput screening with parallel vibrational spectroscopy
WO2007029758A2 (fr) * 2005-09-05 2007-03-15 Canon Kabushiki Kaisha Dispositif de detection
EP1806574A1 (fr) * 2006-01-05 2007-07-11 Université Catholique de Louvain Modification de surface d'éléments optiques pour la détection spectroscopique de molécules et composants organiques.
GB2437981A (en) * 2006-02-15 2007-11-14 Farfield Sensors Ltd Measurement of surface adsorption or desorption
US7812312B2 (en) 2002-04-03 2010-10-12 Johann Wolfgang Goethe-Universitaet Infrared measuring device, especially for the spectrometry of aqueous systems, preferably multiple component systems
FR2965749A1 (fr) * 2010-10-12 2012-04-13 Univ Troyes Technologie Structure multicouche comprenant un métal précieux accroche sur un substrat diélectrique procédé et utilisation associes
CN108713143A (zh) * 2015-09-10 2018-10-26 光束线诊断有限公司 用于分析包含根据每个细胞产生的ftir光谱识别或分选细胞样本的方法、计算机程序和系统
CN112585255A (zh) * 2018-06-26 2021-03-30 伊鲁比斯有限公司 一次性生物反应器及其用途
CN113662537A (zh) * 2016-12-26 2021-11-19 三菱电机株式会社 生物体物质测量装置

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US6464893B1 (en) 2000-05-09 2002-10-15 Pace University Process for preparation of thin metallic foils and organic thin-film-metal structures
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