Quantum Spectroscopy with Undetected Photons for Biomolecular Sensing in the Mid-Infrared
Pith reviewed 2026-05-10 05:38 UTC · model grok-4.3
The pith
A numerical model of a double-pass quantum interferometer reproduces protein mid-infrared absorption spectra from visible-light visibility measurements.
A machine-rendered reading of the paper's core claim, the machinery that carries it, and where it could break.
Core claim
Embedding measured mid-infrared absorption spectra into the numerical model of the double-pass quantum interferometer yields visibility spectra that reproduce the protein absorption bands nearly identically and register temperature-induced alterations to secondary structure, thereby supplying concrete design rules for a practical quantum spectrometer operating with visible light.
What carries the argument
Double-pass quantum interferometer whose visibility pattern, formed by the visible signal photons, encodes the absorption experienced by the undetected mid-infrared idler photons after the classical absorption data is inserted into the model.
If this is right
- Optimal values of nonlinear-crystal length, sample thickness, and mirror-sample distance produce maximum contrast at the specific amide I-II bands.
- The visibility spectra register temperature-induced changes to the protein secondary structure.
- The approach supplies practical design rules for quantum bio-spectroscopy that uses only visible sources and detectors.
- The same model framework applies to both bovine serum albumin and N-terminal pro-brain natriuretic peptide.
Where Pith is reading between the lines
- The method could be tested on other biomolecules whose mid-infrared signatures are already known from classical spectra.
- Hybrid classical-quantum workflows might accelerate validation of new sensing geometries before hardware is built.
- Portable devices for protein diagnostics could become feasible if visible-light components replace mid-infrared sources and detectors.
Load-bearing premise
The numerical model correctly translates the embedded classical absorption data into the quantum interference visibility without needing a physical quantum experiment on the actual protein samples.
What would settle it
Build the double-pass interferometer with the protein sample in the idler path and record whether the measured visibility spectrum at the amide I-II bands matches the simulated spectrum derived from the classical FTIR data.
Figures
read the original abstract
We investigate quantum spectroscopy with undetected photons for protein detection in the mid-infrared spectral region. Classical Fourier-transform infrared spectroscopy of protein samples (bovine serum albumin and N-terminal pro-brain natriuretic peptide) is used as reference to define the sample's mid-infrared absorption, which is then embedded in a numerical model of a double-pass quantum interferometer. We analyse parameters that influence visibility of the interference pattern formed by the signal beams, including the length of nonlinear crystal, sample length and mirror-sample distance. This leads us to a practical quantum spectrometer design with optimal image contrast at the specific amide I-II spectral bands. The simulated visibility spectra reproduce nearly identically the protein absorption features in the mid-IR and reveal temperature-induced changes to the protein secondary structure. Overall, this provides practical design rules for future quantum bio-spectroscopy applications that use only visible wavelength sources and detectors.
Editorial analysis
A structured set of objections, weighed in public.
Referee Report
Summary. The manuscript presents a numerical study of quantum spectroscopy with undetected photons for mid-infrared biomolecular sensing. Classical FTIR absorption spectra of proteins (bovine serum albumin and N-terminal pro-brain natriuretic peptide) are used as reference data and embedded into a model of a double-pass quantum interferometer. The authors examine the effects of nonlinear crystal length, sample length, and mirror-sample distance on interference visibility, optimize these for contrast at the amide I-II bands, and report that the resulting simulated visibility spectra closely reproduce the classical protein absorption features, including temperature-induced shifts in secondary structure. The work concludes with practical design rules for quantum bio-spectrometers that rely only on visible sources and detectors.
Significance. If the numerical model is complete, the results would demonstrate a viable route to mid-IR protein sensing without mid-IR hardware, which has clear practical value for biomolecular applications. The parameter optimization and use of real classical reference data as input are strengths, as is the reported sensitivity to secondary-structure changes. However, the absence of any experimental validation of the quantum interferometer with these samples, combined with the simulation-only nature of the claims, limits the current impact to a design study rather than a demonstrated technique.
major comments (1)
- [Numerical model / quantum spectrometer design] The numerical model of the double-pass interferometer (described in the section on the quantum spectrometer design and simulations) embeds only the amplitude loss derived from classical absorption data. The visibility in undetected-photon schemes depends on the full complex transmission t(ω) = |t(ω)| exp(i φ(ω)) of the idler; the phase φ(ω) must be obtained via Kramers-Kronig relations from the measured absorption or from the real refractive index. If the model omits this phase (or uses only |t|), the simulated visibility spectra cannot be guaranteed to reproduce the absorption features at the amide bands, undermining the central claim that they match 'nearly identically' and reveal temperature-induced changes.
minor comments (2)
- [Abstract] The abstract states that the simulated visibility spectra 'reproduce nearly identically' the protein features but provides no quantitative metric (e.g., RMS deviation or correlation coefficient) for this agreement; adding such a measure would strengthen the presentation.
- [Abstract and conclusion] The parameter values that achieve the 'optimal image contrast' (crystal length, sample length, mirror distance) are not stated numerically in the abstract or conclusion; including them would make the design rules immediately usable.
Simulated Author's Rebuttal
We thank the referee for their careful reading of the manuscript and for highlighting an important technical point regarding the numerical model. We address the comment below and have revised the work to incorporate the suggested improvement.
read point-by-point responses
-
Referee: The numerical model of the double-pass interferometer (described in the section on the quantum spectrometer design and simulations) embeds only the amplitude loss derived from classical absorption data. The visibility in undetected-photon schemes depends on the full complex transmission t(ω) = |t(ω)| exp(i φ(ω)) of the idler; the phase φ(ω) must be obtained via Kramers-Kronig relations from the measured absorption or from the real refractive index. If the model omits this phase (or uses only |t|), the simulated visibility spectra cannot be guaranteed to reproduce the absorption features at the amide bands, undermining the central claim that they match 'nearly identically' and reveal temperature-induced changes.
Authors: We agree with the referee that the visibility in the undetected-photon interferometer depends on the full complex transmission coefficient t(ω) of the idler beam. Our original implementation extracted only the amplitude |t(ω)| from the measured FTIR absorption spectra while omitting the dispersive phase φ(ω). To correct this, we have now applied Kramers-Kronig relations to the absorption data to obtain φ(ω) and have recomputed the interference visibility using the complete complex t(ω). The revised simulations show that the visibility spectra still reproduce the amide I and II absorption features nearly identically, including the temperature-induced secondary-structure shifts reported for both proteins. We have added a new subsection describing the Kramers-Kronig procedure, the resulting phase spectra, and the updated visibility curves, together with a brief discussion of the minor quantitative differences introduced by the phase term. These changes strengthen the central claim without altering the overall conclusions or the practical design rules. revision: yes
Circularity Check
No significant circularity: classical FTIR absorption embedded as independent input into interferometer model
full rationale
The derivation takes measured classical mid-IR absorption spectra (from FTIR on BSA and NT-proBNP samples) as external reference data and embeds them into a numerical model of the double-pass quantum interferometer. Simulated visibility spectra are then computed from this model and shown to reproduce the input absorption features at amide bands. This is a forward simulation using independent external benchmarks rather than any self-definition, parameter fitting to quantum outputs, or load-bearing self-citation chain. No equations reduce the visibility result to the input by construction; the reproduction tests the model's fidelity to the embedded physics. The paper remains self-contained against the cited classical data.
Axiom & Free-Parameter Ledger
axioms (1)
- domain assumption Classical mid-IR absorption data can be directly embedded into the quantum interferometer model without additional quantum corrections or sample-specific effects.
Reference graph
Works this paper leans on
-
[1]
Introduction The mid-infrared (MIR) range of the electromagnetic spectrum, corresponding to wavelengths between approximately 2.5 and 25 μm (4000 to 400 cm⁻¹), is of great importance for environmental sensing, biomolecular detection, and defence applications [1, 2]. This spectral region encompasses the fundamental vibrational modes of most chemical bonds ...
-
[2]
Principles of Quantum Spectroscopy with Undetected Photons Quantum spectroscopy with undetected photons (QSUP) originates from early advances in nonlinear optics, including the first demonstrations of SPDC in the late 1960s and early 1970s, 4 which established the generation of correlated photon pairs for quantum measurements [18]. The core principle enab...
work page 2014
-
[3]
Phosphate buffer solution (PBS) was purchased from ThermoFisher Scientific (Scoresby, Victoria)
Sample preparation and FTIR measurement Lyophilized bovine serum albumin was purchased from Merck (Bayswater, Victoria) and Recombinant Human NT -proBNP was purchased from Millennium science (Mulgrave, Victoria), both proteins were used as supplied. Phosphate buffer solution (PBS) was purchased from ThermoFisher Scientific (Scoresby, Victoria). Protein so...
-
[4]
QSUP simulations We now consider the use of QSUP for label-free biomolecular detection and dynamic protein structure studies in the MIR. The intensity distribution of the signal beams interference in the presence of a biological sample is given by equation (3). Here we use the ATR -FTIR measurement data for the sample transmissivity τ to test feasibility ...
-
[5]
Discussion and Conclusion Our results demonstrate a close agreement between QSUP and FTIR results for the two standard proteins and can, in principle, be extended to sensing of other biomolecules in aqueous solutions. By embedding experimentally measured FTIR spectra of BSA and NT-proBNP into a numerical model of a double-pass interferometer, we numerical...
-
[6]
Data availability statement All the data supporting this study are available upon request to the corresponding authors
-
[7]
An, D. et al. Mid-infrared absorption spectroscopy with enhanced detection performance for biomedical applications. Appl. Spectrosc. Rev. 58, 834–868 (2023). 17
work page 2023
-
[8]
Fakhlaei, R. et al. Application, challenges and future prospects of recent nondestructive techniques based on the electromagnetic spectrum in food quality and safety. Food Chem. 441, 138402 (2024)
work page 2024
-
[9]
Baker, M. J. et al. Using Fourier transform IR spectroscopy to analyze biological materials. Nat. Protoc. 9, 1771–1791 (2014)
work page 2014
-
[10]
Yang, H., Yang, S., Kong, J., Dong, A. & Yu, S. Obtaining information about protein secondary structures in aqueous solution using Fourier transform IR spectroscopy. Nat. Protoc. 10, 382– 396 (2015)
work page 2015
-
[11]
Myshakina, N. S., Ahmed, Z. & Asher, S. A. Dependence of amide vibrations on hydrogen bonding. J. Phys. Chem. B 112, 11873–11877 (2008)
work page 2008
-
[12]
Solntsev, A. S., Kitaeva, G. K., Naumova, I. I. & Penin, A. N. Characterization of aperiodic domain structure in lithium niobate by spontaneous parametric down-conversion spectroscopy. Laser Phys. Lett. 12, 095702 (2015)
work page 2015
-
[13]
Elefante, A. et al. Recent progress in short and mid-infrared single-photon generation: a review. Optics 4, 13–38 (2023)
work page 2023
-
[14]
Ramsay, J., Dupont, S. & Keiding, S. R. Pulse -to-pulse noise reduction in infrared supercontinuum spectroscopy: polarization and amplitude fluctuations. Laser Phys. Lett. 11, 095702 (2014)
work page 2014
-
[15]
Cheng, X. et al. Design of spontaneous parametric down -conversion in integrated hybrid Si x Ny -PPLN waveguides. Opt. Express 27, 30773 (2019)
work page 2019
-
[16]
W., Ramelow, S., Brandstetter, M
Gattinger, P., Schell, A. W., Ramelow, S., Brandstetter, M. & Zorin, I. Quantum Fourier transform infrared spectroscopy: evaluation, benchmarking, and prospects. Appl. Spectrosc. 79, 1737–1746 (2025)
work page 2025
-
[17]
Kalashnikov, D. A., Paterova, A. V ., Kulik, S. P. & Krivitsky, L. A. Infrared spectroscopy with visible light. Nat. Photonics 10, 98–101 (2016)
work page 2016
-
[18]
Paterova, A. V ., Toa, Z. S. D., Yang, H. & Krivitsky, L. A. Broadband quantum spectroscopy at the fingerprint mid-infrared region. ACS Photonics 9, 2151–2159 (2022)
work page 2022
-
[19]
Kumar, M. et al. Controlling visibility in nonlinear interferometry for spectroscopy with undetected photons. APL Photonics 10, 106121 (2025). 18
work page 2025
-
[20]
Moreva, E. et al. Quantum photonics sensing in biosystems. APL Photonics 10, 010902 (2025)
work page 2025
-
[21]
Samimi, S., Ghasemi, Z. & Mohammadi, H. Quantum -enhanced imaging and metrology with undetected photons via squeezed-light homodyne detection. Sci. Rep. 15, 42966 (2025)
work page 2025
-
[22]
Hashimoto, K. et al. Fourier-transform infrared spectroscopy with undetected photons from high-gain spontaneous parametric down-conversion. Commun. Phys. 7, 217 (2024)
work page 2024
-
[23]
Solntsev, A. S., Kitaeva, G. Kh., Naumova, I. I. & Penin, A. N. Measurement of the extraordinary refractive index dispersion in the MIR for Mg:Nd:LiNb O₃ crystals by the use of quasi-phase-matching in a random 1D domain structure. Appl. Phys. B 99, 197–201 (2010)
work page 2010
-
[24]
Burnham, D. C. & Weinberg, D. L. Observation of simultaneity in parametric production of optical photon pairs. Phys. Rev. Lett. 25, 84–87 (1970)
work page 1970
-
[25]
Quantum effects in one -photon and two-photon interference
Mandel, L. Quantum effects in one -photon and two-photon interference. Rev. Mod. Phys. 71, S274–S282 (1999)
work page 1999
-
[26]
Lemos, G. B. et al. Quantum imaging with undetected photons. Nature 512, 409–412 (2014)
work page 2014
-
[27]
Lahiri, M., Lapkiewicz, R., Lemos, G. B. & Zeilinger, A. Theory of quantum imaging with undetected photons. Phys. Rev. A 92, 013832 (2015)
work page 2015
-
[28]
Paterova, A. V ., Maniam, S. M., Yang, H., Grenci, G. & Krivitsky, L. A. Hyperspectral infrared microscopy with visible light. Sci. Adv. 6, eabd0460 (2020)
work page 2020
-
[29]
Placke, M. et al. Mid-IR hyperspectral imaging with undetected photons. in Quantum 2.0 Conference and Exhibition QTu4C.4 (Optica Publishing Group, Washington, D.C., 2024)
work page 2024
-
[30]
Kviatkovsky, I., Chrzanowski, H. M., Avery, E. G., Bartolomaeus, H. & Ramelow, S. Microscopy with undetected photons in the mid-infrared. Sci. Adv. 6, eabd0264 (2020)
work page 2020
-
[31]
Haase, B. E. et al. Phase-quadrature quantum imaging with undetected photons. Opt. Express 31, 143 (2023)
work page 2023
-
[32]
Neves, S. et al. Detection of organic gases in air via quantum Fourier-transform mid-infrared spectroscopy. in Quantum 2.0 Conference and Exhibition QTh4C.7 (Optica Publishing Group, Washington, D.C., 2024)
work page 2024
-
[33]
Kurita, T. et al. Quantum infrared attenuated total reflection spectroscopy. Phys. Rev. Appl. 23, 014061 (2025). 19
work page 2025
-
[34]
Haase, B. et al. Spontaneous parametric down-conversion of photons at 660 nm to the terahertz and sub-terahertz frequency range. Opt. Express 27, 7458 (2019)
work page 2019
-
[35]
S., Kumar, P., Pertsch, T., Sukhorukov, A
Solntsev, A. S., Kumar, P., Pertsch, T., Sukhorukov, A. A. & Setzpfandt, F. Quantum spectroscopy on a nonlinear photonic chip. in 2017 Conference on Lasers and Electro-Optics Europe & European Quantum Electronics Conference (CLEO/Europe -EQEC) 1–1 (IEEE, 2017)
work page 2017
-
[36]
Funding Declaration The authors acknowledge the financial support from Australian Research Council Centre of Excellence in Quantum Biotechnology (CE230100021) and IRTP from UTS
-
[37]
CGP contributed to analysis of results
Author contribution statement ASS and IVK devised the project, MM implemented numerical modelling, MM and MND obtained FTIR results of protein samples, IA and MS consulted on experimental planning. CGP contributed to analysis of results. All authors contributed to the results analysis, manuscript writing and editing
-
[38]
Additional Information The authors declare no competing interests
-
[39]
Figure legends Figure 1. Conceptual scheme for retrieving mid -infrared (MIR) spectroscopic information of proteins using visible (VIS) / near-infrared (NIR) photons. A liquid biopsy sample containing proteins exhibits characteristic vibrational absorption features in the MIR spectral region, such as the Amide I and Amide II bands. In the proposed approac...
work page 2007
-
[40]
Mayerhöfer, T. G., Pahlow, S. & Popp, J. The Bouguer–Beer–Lambert law: shining light on the obscure. ChemPhysChem 21, 2029–2046 (2020)
work page 2029
-
[41]
Zhang, J. & Yan, Y .-B. Probing conformational changes of proteins by quantitative second - derivative infrared spectroscopy. Anal. Biochem. 340, 89–98 (2005)
work page 2005
- [42]
-
[43]
Dong, A., Huang, P. & Caughey, W. S. Protein secondary structures in water from second - derivative amide I infrared spectra. Biochemistry 29, 3303–3308 (1990)
work page 1990
-
[44]
Kalnin, N. N., Baikalov, I. A. & Venyaminov, S. Yu. Quantitative IR spectrophotometry of peptide compounds in water (H2O) solutions. III. Estimation of the protein secondary structure. Biopolymers 30, 1273–1280 (1990)
work page 1990
-
[45]
Venyaminov, S. Yu. & Kalnin, N. N. Quantitative IR spectrophotometry of peptide compounds in water (H 2O) solutions. I. Spectral parameters of amino acid residue absorption bands. Biopolymers 30, 1243–1257 (1990)
work page 1990
-
[46]
Venyaminov, S. Yu. & Kalnin, N. N. Quantitative IR spectrophotometry of peptide compounds in water (H 2O) solutions. II. Amide absorption bands of polypeptides and fibrous proteins in α‐, β‐, and random coil conformations. Biopolymers 30, 1259–1271 (1990)
work page 1990
-
[47]
Chou, P. Y . & Fasman, G. D. β-turns in proteins. J. Mol. Biol. 115, 135–175 (1977)
work page 1977
-
[48]
Usoltsev, D., Sitnikova, V ., Kajava, A. & Uspenskaya, M. Systematic FTIR spectroscopy study of the secondary structure changes in human serum albumin under various denaturation conditions. Biomolecules 9, 359 (2019)
work page 2019
-
[49]
Zhou, X., He, Z. & Huang, H. Secondary structure transitions of Bovine serum albumin induced by temperature variation. Vib. Spectrosc. 92, 273–279 (2017). 29
work page 2017
-
[50]
Holloway, P. W. & Mantsch, H. H. Structure of cytochrome b5 in solution by Fourier-transform infrared spectroscopy. Biochemistry 28, 931–935 (1989)
work page 1989
-
[51]
Olsztyska-Janus, S., Gsior-Gogowska, M., Szymborska-Maek, K., Czarnik-Matusewicz, B. & Komorowsk, M. Specific applications of vibrational spectroscopy in biomedical engineering. In Biomedical Engineering, Trends, Research and Technologies (InTech, 2011)
work page 2011
-
[52]
Srour, B., Bruechert, S., Andrade, S. L. A. & Hellwig, P. Secondary structure determination by means of ATR-FTIR spectroscopy. Methods Mol. Biol. 1635, 195–203 (2017)
work page 2017
-
[53]
Casal, H. L., Köhler, U. & Mantsch, H. H. Structural and conformational changes of β- lactoglobulin B: an infrared spectroscopic study of the effect of pH and temperature. Biochim. Biophys. Acta 957, 11–20 (1988)
work page 1988
-
[54]
Infrared difference spectroscopy
Grdadolnik, J. Infrared difference spectroscopy. Vib. Spectrosc. 31, 279–288 (2003)
work page 2003
-
[55]
Bauelos, S., Arrondo, J. L. R., Goi, F. M. & Pifat, G. Surface-core relationships in human low density lipoprotein as studied by infrared spectroscopy. J. Biol. Chem. 270, 9192–9196 (1995)
work page 1995
- [56]
-
[57]
Reinstädler, D., Fabian, H., Backmann, J. & Naumann, D. Refolding of thermally and urea- denatured ribonuclease a monitored by time-resolved FTIR spectroscopy. Biochemistry 35, 15822–15830 (1996)
work page 1996
-
[58]
Reisdorf, , William C. & Krimm, S. Infrared amide I band of the coiled coil. Biochemistry 35, 1383–1386 (1996)
work page 1996
-
[59]
Gilmanshin, R., Williams, S., Callender, R. H., Woodruff, W. H. & Dyer, R. B. Fast events in protein folding: Relaxation dynamics of secondary and tertiary structure in native apomyoglobin. Proc. Natl Acad. Sci. 94, 3709–3713 (1997)
work page 1997
-
[60]
Reed, R. G., Feldhoff, R. C., Clute, O. L. & Peters, T. Fragments of bovine serum albumin produced by limited proteolysis : conformation and ligand binding. Biochemistry 14, 4578– 4583 (1975)
work page 1975
-
[61]
WETZEL, R. et al. Temperature behaviour of human serum albumin. Eur. J. Biochem. 104, 469–478 (1980)
work page 1980
-
[62]
Carter, D. C. & Ho, J. X. Structure of serum albumin. Advances in Protein Chemistry 45, 153– 203 (1994)
work page 1994
discussion (0)
Sign in with ORCID, Apple, or X to comment. Anyone can read and Pith papers without signing in.