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Letter

pubs.acs.org/JPCL

1 Protein Thermal Conductivity Measured in the Solid State Reveals

2 Anharmonic Interactions of Vibrations in a Fractal Structure

3 Brian M. Foley,† Caroline S. Gorham,† John C. Duda,† Ramez Cheaito,† Chester J. Szwejkowski,‡
‡ ,§,∥
4 Costel Constantin, Bryan Kaehr,* and Patrick E. Hopkins*,†
†
5 Department of Mechanical and Aerospace Engineering, University of Virginia, 122 Engineer's Way, Charlottesville, Virginia 22904,
6 United States
‡
7 Department of Physics and Astronomy, James Madison University, 901 Carrier Drive, Harrisonburg, Virginia 22807, United States
§
8 Advanced Materials Laboratory, Sandia National Laboratories, 1515 Eubank SE, Albuquerque, New Mexico 87123, United States
∥
9 Department of Chemical and Nuclear Engineering, University of New Mexico, 209 Farris Engineering, Albuquerque, New Mexico
10 87106, United States

11 ABSTRACT: Energy processes and vibrations in biological macromolecules such as proteins

12 ultimately dictate biological, chemical, and physical functions in living materials. These energetic
13 vibrations in the ribbon-like motifs of proteins interact on self-similar structures and fractal-like
14 objects over a range of length scales of the protein (a few angstroms to the size of the protein itself,
15 a few nanometers). In fact, the fractal geometries of protein molecules create a complex network of
16 vibrations; therefore, proteins represent an ideal material system to study the underlying
17 mechanisms driving vibrational thermal transport in a dense, fractal network. However,
18 experimental studies of thermal energy transport in proteins have been limited to dispersive
19 protein suspensions, which limits the knowledge that can be extracted about how vibrational energy
20 is transferred in a pure protein solid. We overcome this by synthesizing solid, water-insoluble
21 protein films for thermal conductivity measurements via time-domain thermoreflectance. We
22 measure the thermal conductivity of bovine serum albumin and myoglobin solid films over a range
23 of temperatures from 77 to 296 K. These temperature trends indicate that anharmonic coupling of
24 vibrations in the protein is contributing to thermal conductivity. This first-ever observation of
25 anharmonic-like trends in the thermal conductivity of a fully dense protein forms the basis of validation of seminal theories of
26 vibrational energy-transfer processes in fractal objects.
27 SECTION: Energy Conversion and Storage; Energy and Charge Transport

28
29
30
E nergy processes and vibrations in biological macro-
molecules such as proteins ultimately dictate biological,
chemical, and physical functions in living materials. The vast
over a range of length scales of the protein (a few angstroms to
the size of the protein itself, a few nanometers)6,13,14 that can
be fundamentally different from those found in polymers or
50
51
52
31 functional duties of proteins − from structural building blocks amorphous solids.15,16 In these protein systems, vibrations of 53
32 to molecular recognition, catalysis, and energy transduction1−5 the fractal structure can add additional complexities to 54
33 − are ultimately governed by the energetic vibrations of the understanding vibrational transport. Therefore, proteins 55
34 molecules. Thus, the connection between protein structure and represent an ideal material system to study the underlying 56
35 the pathways of energy flow is a fundamental concern that mechanisms driving vibrational thermal transport in a fractal 57
36 dictates protein functionality and reactivity. These factors drive solid. 58
37 a protein’s applicability and functionality for both native and The nature of the thermal conductivity of proteins was 59
38 artificial applications.6 studied computationally by Yu and Leitner via molecular 60
39 In addition to their fundamental importance in bioprocesses, dynamics simulations.13,17,18 They determined that anharmonic 61
40 proteins present a virtually unexplored avenue to study the vibrational interactions among protein molecules can open up 62
41 fundamentals of thermal transport in naturally occurring an additional channel for thermal conduction in a protein, in 63
42 nanostructured, percolating networks. To date, thermal line with previous theories of thermal conduction in fractal 64
43 conduction in biological materials has often been explored in objects.19−22 In two separate works, they also evaluated the 65
44 the context of amorphous solids and evaluated through thermal conduction in the case of a both spectral13 and gray18 66
45 comparison with some variation of the so-called “minimum mean free paths of protein vibrations. Unfortunately, no 67
46 limit to thermal conductivity”7−12 at elevated temperatures
47 above ∼50−100 K as well as data from atomistic molecular Received: January 26, 2014
48 dynamics simulations. However, the ribbon-like motifs of Accepted: March 7, 2014
49 proteins lead to self-similar structures and fractal-like objects

© XXXX American Chemical Society A dx.doi.org/10.1021/jz500174x | J. Phys. Chem. Lett. XXXX, XXX, XXX−XXX
 The Journal of Physical Chemistry Letters Letter

68 conclusive experimental evidence exists to validate the results

69 from Yu and Leitner nor the aforementioned theoretical work,
70 leaving unanswered questions regarding the role of anharmo-
71 nicity in the thermal conductivity of a protein and a fractal
72 object.
73 In response, we synthesize a series of solid, water-insoluble
74 protein films on substrates to provide a platform to measure the
75 thermal conductivity of these fractal structures. We measure the
76 thermal conductivity of bovine serum albumin (BSA) and
77 myoglobin. Unlike previous works on the thermal conductivity
78 of proteins,23−26 we study solid, insoluble protein structures as
79 opposed to proteins suspended in water or water-saturated
80 proteins. This allows us to directly measure the thermal
81 transport in the network of protein molecules over a range of
82 temperatures without complications from the solution.27,28
83 Using time-domain thermoreflectance (TDTR), we measure
84 the thermal conductivity of these proteins from 77 to 296 K. Figure 2. CD spectra of a protein thin film composed of bovine serum
85 The temperature trends are consistent with previous computa- albumin (BSA) before (closed circles) and after (open squares) heat
86 tional works that show that anharmonic coupling of localized treatment.
87 vibrations in a fractal protein structure contributes to thermal
88 conductivity. 1 h) indicating, as expected, denaturation of constituent 113
89 Water-insoluble protein films were prepared by adapting a proteins at elevated temperatures (≥70 °C). The films that 114
90 previously described method.29 First, proteins were dissolved in we examine in this study are not denatured, as confirmed via 115
91 phosphate-buffered saline (PBS; pH 7.4) to a final concen- CD. 116
92 tration of 3% (wt/vol). This solution was reacted with 0.2 M We measured the thermal conductivity of the protein films 117
93 ethylene glycol diglycidyl ether (EDGE) for 24 h at room with TDTR.32 Detailed specifics of TDTR and data analyses 118
94 temperature. EDGE is a polyepoxy cross-linking reagent that can be found elsewhere.33−35 In brief, TDTR is a pump−probe 119
95 produces protein intermolecular cross-links between amine- measurement technique that utilizes the change in the 120
96 containing residues such as histadine and lysine while thermoreflectance response of a thin metal film36−38 in the 121
97 maintaining overall protein conformation. The reaction was time domain to determine the thermal transport properties of 122
98 dialyzed for 24 h against DI water using a 7 kDa molecular materials adjacent to the metal film. The train of pulses 123
99 weight cutoff membrane. This solution was either drop-cast or emanating from a short-pulsed Ti:sapphire oscillator are 124
100 spin-coated onto oxygen plasma-treated substrates (borosilicate energetically split into the pump-and-probe paths. When 125
101 coverslips and silicon) to achieve thicknesses spanning immediately ejected from the oscillator, the laser pulses are 126
102 micrometers to nanometers. These procedures resulted in centered at 800 nm with 11 nm of bandwidth and are ∼90 fs in 127
f1 103 fully dense protein films, as shown in Figure 1. For data duration. The pump path is modulated at 11.39 MHz, then 128
104 collection with TDTR, we coated all protein samples with a focused to the sample surface generating an oscillatory 129
105 thin Al film, as discussed in more detail later. temperature rise in the Al film at the modulation frequency. 130
The probe pulses are then directed down a mechanical delay 131
stage, focused onto the sample concentric with the pump pulses 132
and back-reflected to a photodiode to monitor the change in 133
reflectance of the probe pulses at the modulation frequency of 134
the pump pulses. At the sample surface, the pump-and-probe 135
pulse widths are unintentionally stretched to ∼400 and ∼200 fs, 136
respectively. The 1/e2 radii of the pump-and-probe pulses on 137
the sample surface were 25 and 6.5 μm, respectively, and we 138
restricted the total laser power incident on the Al surface to a 139
maximum of 25 mW, depending on the sample and 140
temperature. We use lock-in techniques to monitor the small 141
(∼10−4 to 10−5) thermoreflectance signal.39 The monitored 142
data is related to the temperature change of the metal 143
transducer, which at different pump−probe delay times is 144
Figure 1. Scanning electron microscopy cross-section image of a BSA related to the thermal properties of the Al film and the 145
protein film drop-cast onto a silicon substrate. Inset shows higher materials underneath.33−35 146
magnification of the solid protein film. Scale bars = 1 μm. All of the samples were coated with a nominally 90 nm Al 147
film to facilitate TDTR measurements. Because TDTR analyses 148
106 The physical structures of constituent proteins in these films are sensitive to the thickness of this Al film transducer, we 149
107 were characterized using circular dichroism (CD) spectroscopy. measured the film thickness of the Al during each measurement 150
f2 108 Figure 2 shows the far-UV CD spectra of a BSA film spin- with picosecond acoustics.40,41 The proteins films were 151
109 coated on a quartz substrate where characteristic double sufficiently thick (≫1 μm) so that at the 11.39 MHz 152
110 minima at 208 and 222 nm are indicative of intact-helix that modulation frequency of the pump pulses the TDTR response 153
111 comprises the dominant secondary structure of BSA.30,31 The was completely insensitive to the thermal properties of the 154
112 CD signal is substantially attenuated by heating the film (80 °C, substrate. At this pump frequency, we estimate that our 155

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 The Journal of Physical Chemistry Letters Letter

156 measurements sample ∼50−100 nm beneath the Al/protein 11.39 MHz. This is the average heating in the volume sampled 219
157 interface. Therefore, the TDTR data were analyzed with a two- by TDTR (∼50−100 nm beneath the Al/protein interface).33 220
158 layer model of an Al film (the thickness of which was This estimated temperature rise is <1 K for all temperatures 221
159 determined from picosecond acoustics) on a semi-infinite and therefore negligibly affects our reported values. 222
160 protein layer. In addition, because of the combination of the The protein thermal conductivity as a function of temper- 223
161 pump-and-probe spot sizes and the pump modulation ature is shown in Figure 3. The thermal conductivity increases 224 f3
162 frequency, the heat transfer is nearly entirely 1-D in the
163 cross-plane direction.35 We determined the thermal con-
164 ductivity of protein films by fitting the ratio of the in-phase
165 to out-of-phase lock-in output to a two-layer axially symmetric
166 thermal model that accounts for pulse accumulation during the
167 experiment.33−35 We fit t he thermal model to the data by
168 varying the thermal conductivity of the protein. We assume
169 literature values for the heat capacity of Al42 and the heat
170 capacity of the protein. 43,44 We deduce the thermal
171 conductivity of the Al film via the Wiedemann−Franz Law
172 and electrical resistivity measurements. Because of the low
173 thermal conductivity of the proteins, our measurements were
174 completely insensitive to the Al/protein thermal boundary
175 conductance. Therefore, in our analysis, the only fitting
176 parameter was the protein thermal conductivity. We took five
177 to seven TDTR scans at different locations on four different
178 samples of BSA (two on silicon and two on cover glass) and
179 two different samples of myoglobin (both on silicon). The
180 uncertainty in our measurements is determined by considering
181 the repeatability of the measurements at the different sample
182 locations, uncertainty in the local Al film thickness determined Figure 3. Thermal conductivity of BSA and myoglobin (this work),
183 by picosecond ultrasonics, uncertainty in the thermal SiO2,47 and polystyrene (PS)45 as a function of temperature. The
184 conductivity of the Al film, and uncertainty in the heat increase in thermal conductivity in these systems over this temperature
range can be ascribed to anharmonic vibrational interactions.
185 capacities of the proteins. In general, the uncertainty in the
186 measured thermal conductivity of the protein films determined
187 from our TDTR measurements is ∼15%. with temperature, although the values begin to level off upon 225
188 The room-temperature thermal conductivities of our BSA approaching room temperature. We do not heat the sample 226
189 and myoglobin films are 0.231 ± 0.031 and 0.190 ± 0.024 W substantially above room temperature to ensure that we are not 227
190 m−1 K−1, respectively. The thermal conductivities of the BSA denaturing the proteins. For comparison, we also show the 228
191 samples on silicon and glass substrates did not exhibit any thermal conductivity of polystyrene (PS),45 which has been 229
192 difference within the experimental uncertainty. Our BSA previously analyzed in terms of anharmonic coupling of 230
193 measurements agree with previous measurement by Park et vibrations.46 The PS data show very similar trends to our 231
194 al.,24 who determined the thermal conductivity of BSA as 0.265 protein data, which suggest that anharmonic coupling of 232
195 ± 0.08 W m−1 K−1 from various measurements of BSA in water vibrations in the protein structure is contributing to thermal 233
196 solutions. conductivity. As another comparison, we show the thermal 234
197 Unlike measurements of the thermal conductivity of proteins conductivity of SiO2.47 This increase in thermal conductivity 235
198 in solution, our solid protein films allow us to measure the has also been analyzed in terms of anharmonic coupling of 236
199 thermal conductivity of the protein structure at different localized vibrations.46 In other words, much like SiO2 and PS, 237
200 temperatures without having to account for phase changes in anharmonic vibrational coupling contributes to the thermal 238
201 the solution (e.g., freezing of water). We mount our protein conductivity of proteins. 239
202 samples in a liquid-nitrogen-cooled cryostat with optical access In addition to demonstrating thermal conductivity measure- 240
203 for our laser and measure the thermal conductivities of ments of solid proteins over a range of temperatures, one of our 241
204 myoglobin and BSA from 77 K to room temperature. We goals of this work is to lend insight into previous theories on 242
205 only tested the thermal conductivities of the samples on silicon fracton transport. The various fracton theories presented by 243
206 substrates to minimize steady-state heating from the absorbed Orbach and colleagues19−22 claim that an increase in thermal 244
207 laser power.33 For the samples on the silicon substrates, we conductivity over this temperature range is partially due to 245
208 estimate that the steady-state heating from the absorbed laser anharmonic fracton hopping.20 However, the various amor- 246
209 will increase the sample temperature by <1 K over all phous materials that have been analyzed in terms of this fracton 247
210 temperatures. However, for the samples on glass substrates theory are not necessarily fractal, and they can also be well- 248
211 that we tested only at room temperature, we reduced the described by other theories such as the minimum limit to 249
212 incident power but still approximate the steady state temper- thermal conductivity.7−11 In fact, Freeman and Anderson48 250
213 ature rise as ∼20 K. As previously noted, we did not observe discuss that it is not clear what excitations are responsible for 251
214 any difference in measured thermal conductivity so assert that thermal transport in amorphous structures and Cahill and 252
215 this steady-state laser heating difference in the samples on Pohl49 conclude that the fracton theory does not apply to 253
216 different substrates did not change the thermal state of the purely amorphous solids and polymers. Therefore, it is difficult 254
217 material. We expect additional heating in the protein samples to draw any conclusions about the validity of the fracton 255
218 by the absorbed energy from the modulated pump pulses at theories based on previous experiments. However, protein 256

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257 molecules are well-known fractal structures, and our data show not change with temperature according to Yu and Leitner’s 278
258 qualitatively that anharmonic coupling of vibrations in this results and previous simulations by Shenogin et al.13,18,46 As 279
259 fractal network contribute to thermal conductivity. We cannot already established, the increase we observe in thermal 280
260 conclude whether the thermal vibrations in these solid protein conductivity is attributed to anharmonic interactions of the 281
261 samples are indeed fractons or simply localized vibrations; vibrations in the solid, as further supported by the agreement 282
262 however, the observation of anharmonic-like trends in the between in our experimental data and the anharmonic models 283
263 thermal conductivity of these fractal structure will lend insight by Yu and Leitner. (The magnitude of the residuals between 284
264 into future works. our data and the various models is plotted in the bottom panel 285
265 To further the knowledge of how vibrations are contributing of Figure 4.) Because of the uncertainty in our data and our 286
266 to heat transport in fractal proteins, we compare our measured high-temperature limitations to ensure our proteins are not 287
267 thermal conductivity of myoglobin to the molecular dynamics denatured, we can not conclusively determine whether our data 288
f4 268 simulations from Yu and Leitner.13,18 In Figure 4, we plot the shows better agreement with the gray model18 from Yu and 289
Leitner than the spectral model.13 However, this same 290
temperature trend is observed in systems in which anharmoni- 291
cally interacting vibrations are localized to a single mean free 292
path on the order of the intermolecular spacings, such as PS 293
and SiO2 (ref 46). More research must be conducted to 294
determine the length scale of the localization of vibrations in 295
fractal proteins and whether these vibrations are indeed a 296
fracton. 297
The results and discussion above lend further insight into 298
how anharmonic coupling of localized vibrations contribute to 299
thermal conductivity. According to existing theories of thermal 300
conductivity that consider anharmonicity as an independent 301
scattering mechanism as opposed to an independent con- 302
duction channel, anharmonic scattering of vibrations (pho- 303
nons) leads to a decrease in thermal conductivity.50 Contrary to 304
this prediction, in the limit of atomic disorder, it has been 305
shown computationally that three-body interactions increase 306
the thermal conductivity of the vibrational system.51,52 These 307
results have been explained in terms of the anharmonic decay 308
of localized modes in disordered systems, which would 309
otherwise not diffuse thermally.13,18,20,51,52 Furthermore, 310
Leitner et al.53 theoretically estimated the vibrational energy 311
transfer of normal modes, localized and extended, in a 1-D 312
disordered glass finding that the anharmonic contribution to 313
thermal conductivity is provided almost in full by spatially 314
overlapping localized modes. This result is applicable to the 315
protein structure, a randomly arranged heteropolymer struc- 316
tured by bonds of wide-ranging strength,53 where most normal 317
modes of protein and its secondary structure have shown to be 318
Figure 4. (top) Thermal conductivity of myoglobin (squares) as a spatially localized.54 319
function of temperature compared with the various models reported
by Yu and Leitner.13,18 The increase in the thermal conductivity with
In summary, we measured the thermal conductivity of solid, 320

temperature indicates that anharmonic interactions are contributing to water-insoluble protein films of BSA and myoglobin from 77 to 321
the thermal conductivity. Furthermore, on the basis of Yu and 296 K. The thermal conductivities of the proteins increase with 322
Leitner’s computational findings, the observed plateau in the data at increasing temperature. These increasing temperature trends 323
higher temperatures supports the fact that the mean free paths of the indicate that anharmonic coupling of vibrations in the protein is 324
vibrations in proteins are localized to a common length scale. contributing to thermal conductivity. This is consistent with 325
(bottom) Residuals between measured experimental data and the four vibrational transport in nonfractal amorphous solids, such as 326
models shown in the top plot (filled squares: harmonic and constant SiO2 and PS. We cannot conclude whether the thermal 327
MFP; filled circles: harmonic and energy-dependent MFP; open vibrations in these solid protein samples are indeed fractons or 328
squares: anharmonic and constant MFP; open circles: anharmonic and
simply localized vibrations; however, the observation of 329
energy-dependent MFP).
anharmonic-like trends in the thermal conductivity of a fractal 330
structure will lend insight into future works and could form the 331
269 myoglobin data from Figure 3 along with the results from four basis for future validation of seminal theories from Orbach and 332
270 different simulations from Yu and Leitner accounting for: (i) colleagues.19−22 Future computational research could elucidate 333
271 harmonic interactions only with a constant mean free path (i.e., the length scale of the anharmonic vibrational localization 334
272 gray model); (ii) harmonic interactions only with a spectrally length in fractal proteins and whether this vibration is indeed a 335
273 dependent mean free path; (iii) harmonic and anharmonic fracton. 336
274 interactions with a gray model; and (iv) harmonic and Finally, future studies on the heat transport characteristics in 337
275 anharmonic interactions with spectrally dependent mean free solid protein films offer the potential to experimentally realize 338
276 paths. Over the temperature range investigated in our study, if novel phenomena in thermal conduction. For example, as 339
277 anharmonicity was nonexistent, the thermal conductivity would pointed out by Yu and Leitner,17 heat diffusion in a protein is 340

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 The Journal of Physical Chemistry Letters Letter

341 subdiffusive. Therefore, conductance measurements of protein (12) Lubchenko, V.; Wolynes, P. G. The Origin of the Boson Peak 402
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350

351
■ AUTHOR INFORMATION
Corresponding Authors
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413
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353 *E-mail: phopkins@virginia.edu Energy in Proteins. J. Chem. Phys. 2003, 119, 12673−12679. 417

354 Notes (18) Yu, X.; Leitner, D. M. Vibrational Energy Transfer and Heat 418
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355 The authors declare no competing financial interest.

■
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356 ACKNOWLEDGMENTS (20) Alexander, S.; Entin-Wohlma, O.; Orbach, R. Phonon-Fracton 422

357 P.E.H. appreciates financial support from the Office of Naval Anharmonic Interactions: The Thermal Conductivity of Amorphous 423
Materials. Phys. Rev. B 1986, 34, 2726−2734. 424
358 Research (N00014-13-4-0528). B.K. acknowledges support (21) Jagannathan, A.; Orbach, R.; Entin-Wohlman, O. Thermal 425
359 from the U.S. Department of Energy (DOE), Office of Science, Conductivity of Amorphous Materials above the Plateau. Phys. Rev. B 426
360 Office of Basic Energy Sciences (BES), Division of Materials 1989, 39, 13465−13477. 427
361 Sciences and Engineering. This work was partially supported by (22) Alexander, S.; Laermans, C.; Orbach, R.; Rosenberg, H. M. 428
362 the Commonwealth Research Commercialization Fund Fracton Interpretation of Vibrational Properties of Cross-Linked 429
363 (CRCF) of Virginia and the 4-VA mini-grant for university Polymers, Glasses, and Irradiated Quartz. Phys. Rev. B 1983, 28, 4615− 430
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368 Department of Energy National Nuclear Security Adminis- Conductivity of Bovine Serum Albumin: A Tool to Probe the 435
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