submillimeter wave spectroscopy of biological … wave spectroscopy of biological macromolecules...

Submillimeter wave spectroscopy of biological

macromoleculesTatiana Globus

Department of Electrical and Computer Engineering, University of [email protected]

This work is supported by the U.S. DOD under Contract DAAD19-00-1-0402,and in part by U.S.Army NGIC Contract # DASC01-01-C0009

Other participants: Dwight Woolard (ARL, ARO), Boris Gelmont (UVA),Tatyana Khromova (UVA), Maria Bykhovskaya (Lehigh University)GRAs: Xiaowei Li, Ramakrishnan Parthasarathy (UVA)

American Physical Society Meeting 2005, Los AngelesN5-Applications of THz Radiation

APS, March 2005 1

Absorption and Scattering SpectroscopyScattering and absorption spectroscopies utilize the interaction

of an applied electromagnetic field with the phonon (vibration)

field of the material to provide useful structural information .

Raman scattering

I1hνlight

Absorption

APS, March 2005 2

hνvibr

hν1

Ground state Exited state

hν2

hνvibr.

hνvibr. = hν1-hν2

hν1, hν2 >> hνvibr.

hνlight I2

hνvibr.=hνlight

T.Glo us, UVAb

Frequency, cm-10 1000 2000 3000

Abs

orpt

ion

coef

ficie

nt, c

m-1

0

500

1000

1500

2000

I Visible & near IRII -far IRIII -THz

Frequency, THz3 10 30 60 90

III I I

DNA Absorption Spectrum

Absorption spectrum of DNA (our results).

Regions I & II (Studied wellby IR & Raman)- resonances dueto short-range, high energyinteractions

in THz Region III – morespecies specific spectral features of bio molecules are found

FTIR spectroscopy produces high quality spectra in the region II,and can separate overlapping subcomponents in the spectra

APS, March 2005 3T.Globus, UVA

INTERNAL MOLECULAR VIBRATIONSINTERNAL MOLECULAR VIBRATIONS

APS, March 2005 4

In the region III (0.1-10 THz or 2 - 300 cm-1), absorption spectra reflectlow-frequency molecular internal motions or vibrations involving the weakest hydrogen bonds and/or non-bonded interactions between different functional groups within molecules or even between molecules.The resonant frequencies of such motions – phonon modes- are strongly dependent on molecular structure

BondsVibrations of Frequencies

>21 THz (700 cm-1 )

6-27 THz (200-900 cm-1 )Bond angles

Torsion angles< 9 THz (<300 cm-1 )

T.Globus, UVA

WEAK HYDROGEN BONDS

Weakest hydrogen bonds, shown by dots:-C-H ......O--C-H ......N-

-C ...... H-N--C ...... H-O--N-H......O=C-

- weak and have only ~ 5% of the strength of covalent bonds

- multiple hydrogen bonds stabilize the structure of bio-polymers

- hold the two strands of the DNA double helix together, or hold polypeptides together in different secondary structure conformations.


Why THz?

THz spectroscopy reveals structural information quite different from all other methods since it can directly detect weakest hydrogen bonds and non-bonded interactions within biopolymers.

Liquid water absorptionLess water absorption (at list 2 orders)

compare to IR and far-IR. Lessoverlap with water or other analytesabsorption bands. Liquid samples can be characterized.Absorption bands are more narrow in the THz range than in the IR and overlapping of neighboring bands is less.

The availability of multiple resonances for the sensitive measurement of bio-molecule structure.

Spectra are more species specific.


“THE WORLD OF THE DEAD OR OF FUTURE PUNISHMENT“M .N. Afsar &K.J.Button, “Infrared and Millimeter Waves,” V.12, Acad. Press, 1984

“Terahertz gap”The spectral range between the upper end of the microwave and the

lower end of the extreme far IR

APS, March 2005 7

Low energy of sources.Low energy of sources.Low absorptionLow absorption of of biological materialbiological material requires samples with requires samples with large area and thickness which is difficult to make beclarge area and thickness which is difficult to make because ause samples are too fragile.samples are too fragile.PoorPoor reproducibilityreproducibility of experimental results due to of experimental results due to multiple multiple reflectionreflection in measurement systems, responsible for in measurement systems, responsible for artificialartificialfeaturesfeatures; difficulties in sample ; difficulties in sample preparationpreparation, , ininstabilitystability of material.of material.TheThe absenceabsence of goodof good commercially availablecommercially available laboratory laboratory instrumentsinstrumentsPotentially promisingPotentially promising laboratory techniqueslaboratory techniques as as time resolved time resolved spectroscopy and spectroscopy and photomixingphotomixing technology technology are only recently are only recently emergedemerged

T.Globus, UVA

MOTIVATION and GOALS

There is a general need for faster and less expensive techniques

that can provide useful structural information on bio-materials.

Our goal is to demonstrate that THz spectroscopy can be a

fruitful technique even with all mentioned difficulties and by using

commercially available instruments.

T.Globus, UVA APS, March 2005 8

Questions to answer:

Is there something in the very far IR spectra? ((initial prediction of initial prediction of vibrationalvibrational modes in polymer DNA in the 1modes in polymer DNA in the 1--100 cm100 cm--1 frequency range [ 1 frequency range [ E.W.ProhofskyE.W.Prohofsky, K.C. Lu, , K.C. Lu, L.L.Van Zandt and B. F. Putnam, Phys L.L.Van Zandt and B. F. Putnam, Phys LettLett., 70 a, 492 1979; K.V. ., 70 a, 492 1979; K.V. DeviDevi Prasad and Prasad and E.W.ProhofskyE.W.Prohofsky, Biopolymers, 23,1795, 1984]. , Biopolymers, 23,1795, 1984].

What are the reasons why researchers for 20 years failed to achieve reproducible results? Experimental results are not reproducible and are

contradictive. It was not clear what to expect. Can we improve the results?

Can we use the observed features for DNA characterization, identification and discrimination between species?

The key to answer all these questions: we need to know of what we are looking for.

T.Globus, UVA APS, March 2005 9

THEORETICAL PREDICTION OF THz ABSORPTION SPECTRA

Maria Bykhovskaia, B. Gelmont

IR active modes are calculated directly from the base pair sequence and topology of a molecule.InitialInitial approximation was generated and optimized by the approximation was generated and optimized by the program packages program packages JUMNA and LIGAND JUMNA and LIGAND (group of Prof. (group of Prof. LaveryLavery,, Inst.BiologieInst.Biologie Phys.Chim.ParisPhys.Chim.Paris).).

Energy minimum Normal modes Oscillator strengths Spectra

APS, March 2005 10

QUESTIONS:

What do we expect to find in the submillimeter wave range?What is the predictive power of the method?How sensitive are far IR absorption spectra to DNA structure?

Normal mode analysis is applicable to molecules with less than 30 base-pairs

T.Globus, UVA

ENERGY MINIMIZATION AND NORMAL MODE ANALYSIS(in internal coordinates of a molecule)


Molecular potential energy approximated as a function of dynamic variables(q): torsion and bond angles.Conformational energyincluding long distance interactions :

E total = E Van der Waals + EElectrostatic + E HBonds + E Torsion + E Bond angles

Van der Waals and electrostatic interactions; the energy of hydrogen bonds deformations; torsion rotation potentials; stretching deformations of bond angles and of bond length

Two BB--helicalhelical conformation conformation DNA DNA fragments (TA)12(TA)12 with different base pair sequences:

andand thethe AA--helixhelix of double stranded of double stranded RNA Poly[C]RNA Poly[C]..Poly[G]Poly[G]

AAAAAAAAAAAA ATATATATATATTTTTTTTTTTTT TATATATATATA


LOW FREQUENCY NORMAL MODES

0 50 100 150 200 2500

5

10

15

0 50 100 150 200 2500

5

10

15

20Poly (dAdT) Poly (dTdA)

Poly (dA) Poly (dT)

0 200 400 600 8000

5

10

15

Num

ber o

f mod

es

0 200 400 600 8000

5

10

15

20

Vibrational frequency (cm-1)

360 normal modes were found for each sequence with 360 normal modes were found for each sequence with the density higher than 1 the density higher than 1 mode per cmmode per cm--11.. There is almost There is almost no overlapno overlap of of weak bond modesweak bond modes with vibrations with vibrations of of covalent bondscovalent bonds which have frequencies above 750 cmwhich have frequencies above 750 cm--11. .


T.Globus, UVA

APS, March 2005 12

APS, March 2005 13

Absorption Spectra vs. Base Pair Sequence

α(ω) ∼ γω2 Σ (pk)2 / ( (ωk2 - ω2 )2 + γ2 ω2 ), the oscillator decay γk=2 cm-1 ,

the dipole moment

0 100 200 300 400 500

Poly(dAdT)Poly(dTdA)Poly(dA)Poly(dT)

0 100 200 300 400 500

Observed (Powell et al., 1987)

Abs

orpt

ion

Frequency (cm-1)

TheThe spectrum of optical activitiesspectrum of optical activities is veryis very sensitive to the DNA to the DNA base pair sequencebase pair sequence

iii

i me /ap ∑= ,

Maria Bykhovskaia, B. GelmontT.Globus, UVA

APS, March 2005 14

A double stranded 12 base pair RNA homopolymer fragmentPoly[C]-Poly[G] (Maria Bykhovskaia, B. Gelmont)

Absorption spectra for two values of oscillator decay γ =0.5 cm -1 and γ =1 cm –1,

2422201816141210100

20

40

60

80(x+y)z

Frequency, cm

Abs

orpt

ion

coef

ficie

nt, r

el.

units

-1

=0.5 cm -1γ

αα

2422201816141210100

20

40

60

80

(x+y)

z

Frequency, cmA

bsor

ptio

n co

effic

ient

, rel

. uni

ts-1

γ =1 cm -1 α

α

for electric field E perpendicular to the long axes of a molecule ( αx+y) and parallel to the long axes (α z).

For this fragment, the maximum absorption corresponds to E perpendicular to the long molecular axis z.

T.Globus, UVA

Short artificial DNA (Maria Bykhovskaia, B. Gelmont)

B-form: 5'-d(CCGGCGCCGG)-3‘, 10 base pairs per turn,right-handed, has major and minor grooves. A-form: 5'-d(CCCGGCCGGG)-3‘is adopted by dehydratedDNA; it has 11 base pairs per turn, and the base pairs are tilted with respect to the helix axis. A-form is sensitive to humidity and can be changed to B-form.Z-form: 5'-d(GCGCGCGCGC)-3‘- is a left handed DNAhelix in a zig zag pattern with12 base pairs per turn. It adopted in solution at high salt concentration and when reduce salt content it can be changed from left-handed to right-handed.It has no documented biological relevance. DNA exerts a regulatory activity when in Z conformation.

Frequency, cm-1

10 12 14 16 18 20 22 24

Abso

rptio

n, re

lativ

e un

its

0.000

0.002

0.004

0.006

0.008

0.010

BBBA, g=0.5 cm-1, x+y

Optical characteristics depend on conformation

Dry In gel High salt

The two DNA strands are held together by base pairing (hydrogen bonding) between complementary bases. Cytosine ( C ) is always hydrogen bonded to guanine ( G ).


Experimental set up

Bruker IFS-66 spectrometer (Hg- lamp source, He cooled Si-bolometer @ 1.7 º K). Vacuum systems are not shown.

Attachment for reflection measurements.Resolution 0.2 cm-1.Range of interest throughout 10 cm-1 – 25 cm-1.

T.Globus, UVA

APS, March 2005 16

Martin-Pupplett Polarizing Spectrometer


THz FourierTHz Fourier--Transform (FT) spectrTransform (FT) spectroscopyoscopy

Spectral resolution at least 0.25 cm-1 to measure features with 0.5 cm-1

band widthHigh sensitivity (signal to noise) and reproducibility to provide standard deviation better than 0.3% to measure small signals

What is important?Good Instrument performance:

7 samples of BG (5 mg each)

Frequence,cm-1

10 12 14 16 18 20 22 24

Sta

ndar

d de

viat

ion

0.001

0.002

0.003

0.004

0.005

0.006

7 different samples

High transparency of substrates

10 15 20 25

Frequency, cm

0.87

0.89

0.91

0.93

0.95

0.97

0.99

1.01

Tran

smis

sion

CT DNA, 5 mg100%-linePC-membrane, d=5 mkm

-1

Sensitivity Resolution


Challenging ProblemChallenging Problem

Serious problem at THz - all kinds of multiple reflectionsor standing waves in most of measurement systems because of large wavelengths of radiation. These effects cause artificial false resonances.

Frequency, cm-1

10 12 14 16 18 20 22 24

Tran

smis

sion

0.97

0.98

0.99

1.00

1.01

# 206.83, Gor-Tex, d=3 mm

Check for false resonances using thick plates from material with low absorption is important. Ideallyspectrum is close to cos form.


Material for studyMaterial for study

Herring, salmon and calf thymus DNA sodium salts with 6 % sodium salts with 6 % Na content, from Sigma Chemical Co. Na content, from Sigma Chemical Co.

Artificial Artificial short-chained oligonucleotides of known base-pair sequences from Sigma Chemical Co: • Single stranded RNA - potassium salts with the different nucleotide

composition: poly (G), poly (C), poly (A), poly (U),(Guanine (G), Cytosine (C), Adenine (A), Uracyl (U)).

• Double helical RNA - sodium salts: Poly [C] * Poly [G] and Poly [A] * Poly [U].

• DNA, as 5'-d(CpCpGpGpCpGpCpCpGpGp)-3‘ and others with different sequencing, in A, B and Z conformation.

Spores, plasmids, proteins, cellsSpores, plasmids, proteins, cellsBioBio--materials in solutionsmaterials in solutions


APS, March 2005 21

Sample preparationSample preparation

Simple techniques has been developed to fabricate large area, thin, stable samples

Free-standing films and films on substrates are prepared from the water gel. Film thickness 2 µm - 250 µm.

The ratio of water to dry material in the gel from 5:1 to 30:1.

Thin polycarbonate membranes, polyethylene or Teflon films with ~98% transmission are used as supporting substrates in some cases.

To receive good resolution, samples of at least 1/2" diameter are fabricated.

Samples are aligned to receive preferable orientation of long molecule axes in one direction. Good alignment enhances the sensitivity.

T.Globus, UVA

APS, March 2005 22

2422201816141210880.25

0.35

0.45

0.55

0.65

d=0.125 mm d=0.205 mm

Frequency, cm

Tran

smis

sion

-1

n=2.2 n=1.9

nd = m λ 4

extr

Reproducibility vs. orientation and interference effects

λextr - the wavelength of transmission extremad - the film thicknessm - the order of extremum.n- refractive index ~ 1.7 - 2.3

Poly[A], d~160 µm

Frequency, cm-1

8 10 12 14 16 18 20 22 24

Tran

smis

sion

0.50

0.52

0.54

0.56

0.58

0.60

02/0402/05

m=2

m=1

Resonance features are resolved on the envelope of the wide interference pattern.

Same orientation

These kind of interference features were initially considered as resonance modes in bio materials.

T.Globus, UVA

Absorption coefficient

2422201816141210100.45

0.55

0.65

0.75

0.85

0.95 PolyCPolyG

PolyC-PolyG

PolyAPolyUPolyA-PolyU

Frequency, cm

Tran

smis

sion

-1

The interference pattern is not obvious in transmission of thin films(thickness between 15 and 70 µm).

Absorption coefficient spectra are derived by interference spectroscopy technique(IST) for proper modeling of the multiple reflection behavior.

T.Globus, UVAAPS, March 2005 23

Material texture

Image of the Salmon DNA sample in polarizing microscope (free standing).

Film thickness about 10 µm.

Gel concentration 1:10.

DNA, as a rod-like polymer, spontaneously forms ordered liquid crystalline phases in aqueous solution with the long molecular axis preferentially aligned in one direction.

In drying process, DNA solution undergoes a series of transitions and film samples are characterized by their microscopic textures with periodic variations in refractive index and fringe patterns observed in polarizing microscope.

The film texture depends on the concentration of molecules in solution and on drying conditions.


APS, March 2005 25

Absorption coefficient at two orientations

For Poly[A]-Poly[U] fragments, absorption is higher and resonance structure is much more pronounced with electric field of radiation E perpendicular to the long axes of molecules Z.

Poly [A]-Poly[U], d=16 µm

Frequency, cm-1

10 15 20 25

Abs

orpt

ion

coef

ficie

nt, c

m-1

0

50

100

150

E perp Z E//Z

Documented strong anisotropy of optical characteristics ofbiological molecules at THz.

E

z

x+y

x+y

Ez

a b

Sample position with electric field (a) perpendicular and (b) parallel to the long-axis of the molecule z.

Change with sample rotation.Change with sample rotation.

T.Globus, UVA

Experiment and Modeling

Many of the initial successful measurements of the THz absorption properties of biological materials have been performed at the University of Virginia.

Evidence of multiple resonances in THz transmission spectra with a high degree confidence in recognition of bio- molecules has been demonstrated.

Direct comparison of experimental spectrum (red) with theoretical prediction (blue) for a short chain DNA fragment with known structure.

Reasonably Good correlationvalidates both, experimental and theoretical results.From the width of the vibrational modes:

oscillator decay γ =0.5 cm -1

relaxation time τ =7 10-11 s

APS, March 2005 26

Poly [C]- Poly [G] d=6.5 µm

Frequency, cm-1

10 12 14 16 18 20 22 24

Abs

orpt

ion

coef

ficie

nt, c

m-1

0

10

20

30

40 measured calculated, γ=0.5 cm-1, E perp Zcalculated, E // Z

T.Globus, UVA

Long term reproducibility

Salmon DNA

Frequency, cm-1

10 12 14 16 18 20 22 24

Tran

smis

sion

0.68

0.70

0.72

0.74

0.76

0.78

0.80

0.82

0.84#220.29, 10/31/02#220.39, 10/31/02#222.12, 11/07/02#225.23, 11/14/02#227.07, 11/21/02#230.10, 12/11/02

Improved technique for solid film sample preparation:good alignmentreduced amount of material from 15-20 mg to 1- 3 mg for one samplereproducibility better than 0.5%

Period of 45 days


Single- and double stranded Salmon-DNA

Wavenumber, cm-1

10 12 14 16 18 20 22 24

Abso

rptio

n C

oeffi

cien

t, cm

-1

40

60

80

100double stranded, d = 24.3 µm single stranded, d = 5.8 µm

Wavenumber, cm-1

10 12 14 16 18 20 22 24

Ref

ract

ive

Inde

x (d

s)

2.1

2.2

2.3

2.4 double stranded

Ref

ract

ive

Inde

x (s

s)

2.7

2.8

2.9

3.0

3.1

single stranded

Absorption for ss-DNA ~ 20 % higher than for ds-DNA.Additional peaks in α at 11.2 cm-1,13.4 cm-1 and 14.8 cm-1 for ss-

DNA.Higher n for ss-DNA.

THz spectra are sensitive to conformation change that can be used for monitoring folding-unfolding of DNA


THz spectra of Biopolymers in water (gel)

Biological materials in an aqueous form (or gel) can be characterized as well as in solids.

Signature is strong. Relative change in the peak up to 10-30%.Spectra are not disturbed by water absorption at THz (except at 18.6 cm-1).High sensitivity of spectra to orientation.

Lysozyme

Frequency, cm-1

10 12 14 16 18 20 22 24

Tran

smis

sion

0.18

0.20

0.22

0.24

0.26

0.28

0.30

0.32

0.34

30 deg90 deg 120 deg

Importance: all living matter is in a liquid form

Possible applications:

APS, March 2005 29

structural characterization of proteins and DNA at THz; monitoring biological processes.

Disturbance at 18.6 cm-1 is due to

absorption of water vapor in air.

T.Globus, UVA

Structural phase transition

Herring DNA, gel 1:12

Frequency,cm-1

10 12 14 16 18 20 22 24

Tran

smis

sion

0.02

0.04

0.06

0.08

0.10

0.12

0.143 713182328 3338

Time, min

Changing transmission spectrum of liquid herring DNA sample with time after defrosting.

Herring DNA , gel 1:10

Time, sec

100 1000

Abs

orpt

ion

coef

ficie

nt, c

m-1

0

100

200

300

400

500

600

700

24.1 cm-1

23 15.9510.95

Several vibrational modes

APS, March 2005 30

Temperature of structural transitions is close to RT and is sensitive toenvironmental conditions, including humidity.

Very high reproducibility of resonant features up to transmission level 90 %.

Sensitivity limit in aqueous form as well as the possibility to measurepolarization effects require clarification.

T.Globus, UVA

Possible applications of THz spectroscopy

Wide-range of biomedical applications based on close relationship between structure and spectra, including monitoring changes in molecular conformation in real time

real-time analysis of protein binding for transportprotein binding with antibodies, specificity interactions between proteins and nucleic acidsbinding stability studies of drug-protein and vitamin-protein systemsdisease diagnostic

Systems for bio-detection and identification

Remote sensing of biochemical agents

T.Globus, UVAAPS, March 2005 31

Bio-Medical Application: Disease diagnostic

Cancer Cells frozen

Frequency, cm-1

10 12 14 16 18 20 22 24

Tran

smis

sion

0.44

0.46

0.48

0.50

0.52

0.54

bladder prostate

Cancer cellsCancer cells suspended in buffer solutionsuspended in buffer solution (Phosphate(Phosphate--Buffered Buffered Saline) with the ratio of dry material to liquid ~ 1:10 were meSaline) with the ratio of dry material to liquid ~ 1:10 were measuredasured

Spectra of prostate and bladder cancer cellsTHz spectroscopy appears to be a promising approach toward discriminating between different tumor phenotypes.

Can we use tissue for cancer characterization?


REFERENCES

M. Bykhovskaia, B. Gelmont, T. Globus, D.L.Woolard, A. C. Samuels, T. Ha-Duong, and K. Zakrzewska, “Prediction of DNA Far IR Absorption Spectra Basing on Normal Mode Analysis”, Theoretical Chemistry Accounts 106, 22-27 (2001).

T. Globus, L. Dolmatova-Werbos, D. Woolard, A.Samuels, B. Gelmont, and M. Bykhovskaia, "Application of Neural Network Analysis to Submillimeter-Wave Vibrational Spectroscopy of DNA Macromolecules ,” Proceedings of the International Symposium on Spectral Sensing Research, p.439 (2001), Quebec City, Canada, 11-15 (June 2001).

D. L. Woolard, T. R. Globus, B. L. Gelmont, M. Bykhovskaia, A. C. Samuels, D. Cookmeyer, J. L. Hesler, T. W. Crowe, J. O. Jensen, J. L. Jensen and W.R. Loerop. “Submillimeter-Wave Phonon Modes in DNA Macromolecules", Phys. Rev E. 65, 051903 (2002).

D.L. Woolard, E. R. Brown, A. C. Samuels, T. Globus, B. Gelmont, and M. Wolski “Terahertz-frequency Spectroscopy as a Technique for the Remote Detection of Biological Warfare Agents ,” Proceedings to the 23th Army Science Conference, Orlando, Florida, 2-5 (2002).

T. Globus, D.Woolard, M. Bykhovskaia, B. Gelmont, L. Werbos, A. Samuels. “THz-Frequency Spectroscopic Sensing of DNAand Related Biological Materials”in Selecting Topics in Electronics and System, Vol 32: Terahertz Sensing Technology, Vol 2, pp.1-34, World Scientific (2003) .

T. Globus, M. Bykhovskaia, D. Woolard, and B. Gelmont , “Sub-millimeter wave absorption spectra of artificial RNA molecules ,”Journal of Physics D: Applied Physics 36, 1314-1322 (2003).

T. R. Globus, D. L. Woolard, T. Khromova, T. W. Crowe, M. Bykhovskaia, B. L. Gelmont,. Hesler, and A. C. Samuels, “Thz-Spectroscopy of Biological Molecules,” Journal of Biological Physics, V29, 89-100 (2003).

T. Globus, T. Khromova, D. Woolard and B. Gelmont, “Terahertz Fourier transform characterization of biological materials in solidand liquid phases”, Chemical and Biological Standoff Detection in the Terahertz Region, Providence, RI, Oct 2003, Proceedings ofSPIE, Vol. 5268-2, pp.10-18 (2004).

T. Globus, D. L. Woolard, A.C. Samuels, T. Khromova, J. O. Jensen “Sub-Millimeter Wave Fourier Transform Characterisation of Bacterial Spores”. Proceedings of the International Symposium on Spectral Sensing Research, Santa Barbara, California, 2-6 June 2003, file://F:\isssr2003\index.htm (2004).

T. Globus, D. Woolard, T. Khromova, R. Partasarathy , A. Majewski, R. Abreu , J. Hesler, S.-K. Pan, G. Ediss, “Terahertz signaturesof biological-warfare-agent simulants”, International Symposium on Defense and Security: Orlando, FL, Apr.2004, Proceedings of SPIE Vol. 5411-5 (2004).

T. Globus, R. Parthasarathy, T. Khromova, D. Woolard, N.Swami, A. J. Gatesman, J. Waldman, “Optical characteristics of biological molecules in the terahertz gap”, Proceedings of SPIE Vol. 5584-1 “Chemical and Biological Standoff Detection II” OE04 Optics East, Phyladelphia (Oct. 2004).

T. Globus, D. Theodorescu, H. Frierson , T. Kchromova , D. Woolard, “Terahertz spectroscopic characterization of cancer cells”, Proceedings of SPIE, The Advanced Biomedical and Clinical Diagnostic Systems III, v. 5692-42, San Jose (2005).


submillimeter wave spectroscopy of biological … wave spectroscopy of biological macromolecules...

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