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Physical Insights into Materials and Molecular Properties

Efficient Electron Hopping Transport through Azurin-Based Junctions
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  • Carlos Roldán-Piñero
    Carlos Roldán-Piñero
    Departamento de Física Teórica de la Materia Condensada, Universidad Autónoma de Madrid, E-28049 Madrid, Spain
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  • Carlos Romero-Muñiz
    Carlos Romero-Muñiz
    Departamento de Física de la Materia Condensada, Universidad de Sevilla, PO Box 1065, 41080 Sevilla, Spain
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    Orcidhttps://orcid.org/0000-0001-6902-1553
  • Ismael Díez-Pérez
    Ismael Díez-Pérez
    Department of Chemistry, Faculty of Natural & Mathematical Sciences, King’s College London, Britannia House, 7 Trinity Street, London SE1 1DB, U.K.
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    Orcidhttps://orcid.org/0000-0003-0513-8888
  • J. G. Vilhena
    J. G. Vilhena
    Departamento de Física Teórica de la Materia Condensada, Universidad Autónoma de Madrid, E-28049 Madrid, Spain
    Condensed Matter Physics Center (IFIMAC), Universidad Autónoma de Madrid, E-28049 Madrid, Spain
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    Orcidhttps://orcid.org/0000-0001-8338-9119
  • Rubén Pérez
    Rubén Pérez
    Departamento de Física Teórica de la Materia Condensada, Universidad Autónoma de Madrid, E-28049 Madrid, Spain
    Condensed Matter Physics Center (IFIMAC), Universidad Autónoma de Madrid, E-28049 Madrid, Spain
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    Orcidhttps://orcid.org/0000-0001-5896-541X
  • Juan Carlos Cuevas
    Juan Carlos Cuevas
    Departamento de Física Teórica de la Materia Condensada, Universidad Autónoma de Madrid, E-28049 Madrid, Spain
    Condensed Matter Physics Center (IFIMAC), Universidad Autónoma de Madrid, E-28049 Madrid, Spain
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    Orcidhttps://orcid.org/0000-0001-7421-0682
  • Linda A. Zotti*
    Linda A. Zotti
    Departamento de Física Teórica de la Materia Condensada, Universidad Autónoma de Madrid, E-28049 Madrid, Spain
    Condensed Matter Physics Center (IFIMAC), Universidad Autónoma de Madrid, E-28049 Madrid, Spain
    *Email: [email protected]
    More by Linda A. Zotti
    Orcidhttps://orcid.org/0000-0002-5292-6759
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The Journal of Physical Chemistry Letters

Cite this: J. Phys. Chem. Lett. 2023, 14, 49, 11242–11249
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https://doi.org/10.1021/acs.jpclett.3c02702
Published December 7, 2023

Copyright © 2023 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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We conducted a theoretical study of electron transport through junctions of the blue-copper azurin from Pseudomonas aeruginosa. We found that single-site hopping can lead to either higher or lower current values compared to fully coherent transport. This depends on the structural details of the junctions as well as the alignment of the protein orbitals. Moreover, we show how the asymmetry of the IV curves can be affected by the position of the tip in the junction and that, under specific conditions, such a hopping mechanism is consistent with a fairly low temperature dependence of the current. Finally, we show that increasing the number of hopping sites leads to higher hopping currents. Our findings, from fully quantum calculations, provide deep insight to help guide the interpretation of experimental IV curves on highly complex systems.

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The field of protein electronics has flourished remarkably over the past decade. (1) The interest in these systems is mainly triggered by the highly efficient charge-transfer that proteins can exhibit over long distances, (2,3) besides their role in extremely important processes such as in the respiratory and photosynthetic chains. (4,5) However, experimental advances have also enabled the study of electron transport through proteins incorporated in solid-state junctions. (6,7) This has paved the way for the development of future electrical devices based on proteins as active elements, as well as their use in sensors and biocompatible devices. (8) In addition, interesting mechanical, self-assembly, chemical recognition, and optoelectronic properties have been revealed which could be exploited in the development of such new-generation devices. Among various types of proteins studied in the field, the blue-copper azurin from Pseudomonas aeruginosa has been analyzed quite extensively. (9−13) These studies brought to light several surprising electron-transport properties: these include the possibility of inducing drastic changes in the gate-voltage dependence via a single amino acid mutation, (14) the lack of temperature dependence down to 4 K (12,15,16) (which was interpreted as an indication of coherent tunneling), and the considerably high conductance values (up to 10–5G0 in single-protein experiments (17)) observed despite its large size. (17) Nevertheless, to date, the exact nature of the transport mechanism through this protein is still the subject of a long-standing debate; (15,18) several types of processes such as 2-step tunneling, (14) fully coherent transport, (19) and carrier-cascade (20) have been proposed. Recently, some of us have shown that fully coherent tunneling through a single-azurin junction would lead to extremely low conductance values as compared to those observed in experiments. (18) This was deduced from a density functional theory (DFT)-based study, which involved a high number of geometrical structures obtained via molecular dynamics simulations (MD), reproducing a broad range of structures likely formed in STM experiments. A subsequent study of ours revealed that, within the same transport mechanism, the role of the central metallic ion would not be as relevant as expected compared to other residues of the protein. (21) These findings have cast doubts on the actual role of fully coherent transport with respect to other types of transport processes (such as sequential tunneling, for instance), which were otherwise suggested. (14) Clarifying such a basic issue is paramount in the prospect of developing protein-based electronics and optimizing the performance of any electrical device incorporating these kinds of systems. Therefore, in order to shed light on this puzzle, we hereby extend our investigation on azurin-based junctions to the analysis of an incoherent type of electron transport, which until now was only tackled by means of simple models (15) (which do not include the complexity of the whole electronic structure of these systems). In particular, we have analyzed a hopping process through either the Cu ion or a histidine residue which was previously found to be relevant in the tunneling process. (21) We will show that the hopping currents can be higher or lower than those obtained in a fully coherent transport depending on structural details of the junctions such as the tip–protein contact. These also affect the asymmetries in the IV curves, depending on the different coupling established with the electrodes.

More specifically, we have computed current–voltage (IV) curves based on an incoherent-transport (hopping) model for gold–azurin–gold junctions, such as those displayed in Figure 1a. The geometrical structures were obtained via MD simulations, the details of which were reported in previous works. (18,22) There, the study of their electronic-structure properties is also presented. They were extracted via a fully quantum approach based on DFT calculations which were performed by using the code OpenMX. (23,24) We started our investigation by focusing on the Cu ion, which previous literature (14,15,25) indicated as the main player in the electron transport through this protein. In the model employed in this study, an electron travels between a substrate and a tip via hopping on the Cu ion (which is located in the central area of the protein), as depicted in Figure 1b. The black arrows indicate the transfer rates for each of the two steps in each direction. In the following, we will refer to the substrate and tip as the left and right electrode, respectively.

Figure 1

Figure 1. (a) Initial (i, iii) and final (ii, iv) geometries for the MD simulations mimicking junction formation through blinking (left) and side-indentation (right), respectively. (b) Schematic representation of the electron-transport mechanism taking place in a metal–azurin–metal junction via hopping through the Cu ion. (c) Schematic representation of the three cases considered for the level alignments.

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In the framework of the Marcus theory, (26−28) for a given bias voltage V applied between left and right electrode, the transfer rates between the leads and the Cu ion can be calculated as

kL→=2ΓLℏ∫−∞∞dEf(E−μL)Wox(ε0(V),μL)
(1)
kL←=2ΓLℏ∫−∞∞dEf(μL−E)Wred(ε0(V),μL)
(2)
kR→=2ΓRℏ∫−∞∞dEf(μR−E)Wred(ε0(V),μR)
(3)
kR←=2ΓRℏ∫−∞∞dEf(E−μR)Wox(ε0(V),μR)
(4)
where f(E) are the Fermi distribution functions, while μL/R is the voltage-induced displacement of the chemical potential of either the left or the right metallic electrode, calculated as
μM={−(1/2)eVforM=L(1−1/2)eVforM=R
(5)
In our model, the Fermi level of the left (right) electrode is shifted downward (upward) in energy for positive bias, while it is shifted in the opposite directions for negative bias. Wox/red are distribution functions given by
Wox(ε̃0(V),μM)=e−[λ−(μM+E)+ε̃0(V)]2/4λkBT4πλkBT
(6)
Wred(ε̃0(V),μM)=e−[λ+(μM+E)−ε̃0(V)]2/4λkBT4πλkBT
(7)
where λ is the reorganization energy of the hopping center and ε̃0 is the position of the level, which changes as a function of the bias voltage (see below for further details). Here, ΓL/R is the level broadening associated with the coupling with the left or right electrode. They were calculated as
ΓM=πtM2ρM
(8)
where ρM is the average density of states per atom in the left or right electrode while tM can be interpreted as a through-bridge tunneling matrix element. (27) All quantities (except for the reorganization energy) were obtained from the output of the DFT calculations performed on the whole metal–protein–metal junctions. In particular, the evaluation of tM required two distinct postprocessing calculations for the left and right metal–protein interfaces. In our procedure, the total Hamiltonian H is first divided into blocks as follows:
H=(HLHL,ProtHL,CuHL,RHProt,LHProtHProt,CuHProt,RHCu,LHCu,ProtHCuHR,ProtHR,LHR,ProtHR,CuHR)
(9)
where HL, HCu, and HR are the blocks relative to the left electrode, the Cu ion, and the right electrode, respectively, while HProt is the block corresponding to the protein deprived of the Cu orbitals. The off-diagonal terms correspond to the interactions among these four main components. Within the limit of validity of perturbation theory, tL is then given by HL,Protg(E)HProt,Cu, whereas tR is given by HCu,Protg(E)HProt,R. Here, g(E) is Green’s function corresponding to the protein deprived of the Cu-ion, which acts as the bridge in both steps (metal–Cu and Cu–metal). Obviously, for each process, the residues in the protein which are spatially located far away from the direct path between Cu and the electrode do not contribute significantly. More specifically, the Green’s function g(E) is calculated as
g(E)=[ESProt−HProt]−1
(10)
SProt being the corresponding block of the overlap matrix. The dependence of the uncorrected position of the level ε0 on the coupling with the electrodes and the bias voltage was taken into account by calculating it as follows:
ε̃0(V)=ε0+εC−(1/2−r)eV
(11)
Here, εC is a correction that we apply to the molecular orbitals of the protein in order to address the inaccuracy induced in the energy-level alignment by the use of the DFT-GGA approach. This was achieved by means of a scissor-like correction (29) which results in an increase of the HOMO–LUMO gap.

The quantity r serves the purpose of addressing the energy displacement of the level ε0 due to the coupling with the electrodes.

r=ΓRΓL+ΓR
(12)

Finally, the current was computed as (15,27)

I(V)=−ekL→(V)kR→(V)−kL←(V)kR←(V)kL→(V)+kR→(V)+kL←(V)+kR←(V)
(13)

In order to account for a possible role of more than one hopping site, we also explored the use of a three-site model, in which the central site is the metal ion whereas the other two are the two portions of protein comprised between the ion and the electrode on each side. In this case, the analytical expression of the current becomes more cumbersome. The details about the extraction of the current values in this case can be found in the SI. For the sake of comparison, for selected cases, we compared the current values with those obtained within a fully coherent mechanism. In this case, the current is given by the Landauer formula

I(V)=2eh∫−∞∞T(E,V)[fL(E)−fR(E)]dE
(14)
where fL/R(E) are the Fermi functions of left and right electrodes. The transmission T(E, V) has been computed by Green’s function techniques as described in ref (18) upon applying the same gap correction as for the hopping model (see below for details).

We now turn to analysis of the computational results. We have considered single-protein junctions that mimic structures likely to be obtained with STM-based techniques. In the present study, these include two main sets of geometries: (i) junctions obtained by simulating the blinking technique and (ii) junctions obtained by simulating a lateral indentation (Figure 1a). In the former, the tip is positioned in the proximity of the protein, avoiding physical contact. However, thermal fluctuations induce continuous attachment and detachment from the tip. Jumps in the current signal are detected whenever chemical bond is established. (14,30−33) In the latter, the tip approaches the protein sideways, while it is kept at a fixed distance from the surface. As mentioned before, the study of the mechanical and electronic properties of these structures (obtained by MD and uncorrected DFT-GGA) was reported in previous works. (18,22)

In the present study, we have considered three possible scenarios for the zero-bias alignment of the protein with respect to the Fermi level of the electrodes (see Figure 1c): the Fermi level lying in the middle of the HOMO–LUMO gap (i) and either the HOMO (ii) or the LUMO (ii) being very close to the Fermi level. For the sake of simplicity, we will refer to these three cases as symmetric, HOMO-dominated, and LUMO-dominated, respectively. For all of them, based on previous literature, (34) the size of the HOMO–LUMO gap was increased by 1 eV with respect to the GGA value. The reason for considering these three representative cases lies in the conflicting information reported in the literature regarding the level alignment for this system. (14,21,34−37) For small organic molecules, the position of the frontier orbitals can be extracted via differences of total energies of neutral and charges states. (29,38) DFT calculations of charged states of a complex system such as the entire azurin protein (almost 2000 atoms), however, are not straightforward and may easily lead to incorrect results. Therefore, we prefer to turn to analyzing these three clear-cut situations so as to cover all possibilities. Note that in any case they would also correspond to the different scenarios induced by applying different gate-voltage values.

A key ingredient in Marcus theory is given by the reorganization energy. Over the years, various values have been reported for the blue-copper azurin. (34,39−41) For the present work, we employed a value of 0.5 eV. Nevertheless, in the SI we show examples of curves obtained with different reorganization-energy values.

Previous literature indicated the Cu ion as the main player in electron transport through azurin junctions. (14,15,25) In the case of the HOMO-dominated and the symmetric case, this seems to be plausible given the presence of Cu orbitals among the highest occupied energy levels of the protein. (18,37) Thus, the Cu ion was chosen as the hopping site. For the LUMO-dominated case, however, the same choice does not appear as suitable, since the Cu unoccupied states lie well above the Fermi level. Indeed, our DFT calculations revealed that in these structures, the LUMO is not localized on the Cu ion but rather on the residue HIS35, which is positioned between the Cu ion and the surface. Consequently, for the LUMO-dominated case, this residue was chosen as the hopping site. For this, the same reorganization-energy value as that for Cu was chosen (curves obtained with different values are shown in the SI). It should be noted that the HIS35 residue was already found to be particularly relevant within a fully coherent transport. (21)

Figure 2 displays the I(V) curves obtained for the blinking (a) and side indentation (b). For each case, we show three sets of curves, corresponding to three representative time frames for the blinking and three different tip–protein distance values for the lateral indentation. Such a distance was calculated between the Cu ion and the center of the lowest tip layer. The majority of the curves shown in this figure exhibits some degree of asymmetry, their values at positive voltage being either higher or lower than in the negative range depending on the coupling with the leads. It is well-known, indeed, (26) that asymmetries in IV curves mostly originate from geometrical asymmetries in the junction. In fact, differences in the coupling at the molecule–metal interface can affect the voltage profile by inducing an energy shift in a molecular orbital in the same direction as the chemical potential of the electrode with which it is more strongly coupled (as described, in our model, by eq 5). The curves in Figure 2, in particular, seem to reflect the differences in the tip–protein contact between the two schemes. In the final steps of the lateral indentation, the tip becomes significantly close to the Cu complex, making the Cu–lead coupling on that side larger than that on the opposite side. Conversely, in the blinking process, a separation between the α helix and β barrel is induced by formation of the metal–protein contact, (22) making the Cu–tip coupling weaker than on the surface side. In the symmetric scenario considered in our model, for instance, in the case for which the coupling between the Cu ion and the tip becomes more relevant than the Cu–surface coupling, values at positive bias become higher than those at negative bias. The opposite applies to the reversed situation. This is particularly visible in the symmetric case for the lateral indentation, where the Cu–tip coupling increases as the tip approaches the protein, reversing the asymmetry (blue curve vs red and green curves). This does not happen for the blinking case, since there the Cu–tip coupling is much lower than in the side indentation. Interestingly, the same reasoning does not seem to apply to the HOMO- and LUMO-dominated cases, where this effect seems to be counteracted by the proximity of the orbital to the Fermi level. An in-depth discussion of this issue may be found in the SI. It should be noted that such a detailed analysis of the asymmetries is possible thanks to having obtained the whole electronic structure of the entire metal–protein–metal junction at the DFT level and to having calculated the coupling elements by means of the perturbation-theory approach described above. It is also worth mentioning that asymmetries in the IV curves were indeed observed in some of the experimental measurements on this protein (see, for instance, Figure S3 of ref (42)).

Figure 2

Figure 2. Hopping currents through one site in the blinking (a) and lateral (b) scheme for the HOMO-dominated, symmetric, and LUMO-dominated cases.

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Overall, the lateral indentation yields higher current values than the blinking. It should be noted that the same was observed for the fully coherent transport through the same system and is mainly due to the shorter tip–surface distance in the side-indentation junctions. (18) For the blinking method, we find that the highest current values are obtained within the HOMO-dominated scheme. For the lateral indentation, instead, the highest values are obtained for the LUMO dominated case. This is probably due to the strong coupling between the surface and residue HIS35, which is the hopping site in this case. As this residue is positioned between the Cu ion and the surface, however, this effect fades away in the blinking scenario, where the larger HIS35–tip distance leads to a decrease in the current.

We now turn to analyzing the temperature dependence of the current, which has been the subject of several studies focused on the azurin. (9) In Figure 3a, we report, as an example, the current as a function of the inverse of the temperature for a range between 10 and 500 K for two selected cases (t = 466.6 ns for the blinking and d = 2.54 nm for the side indentation), fitted to the following exponential equation:

log10[I(V=300mV)1A]=A−B·1000KT
(15)

Figure 3

Figure 3. (a) Temperature dependence of the one-site hopping currents obtained for blinking (at t = 466.6 ns) and for the lateral indentation (for d = 2.54 nm). (b) Barplot with the values of the fitting parameter B of eq 15 for all cases considered.

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This fit was performed on all of the MD simulation frames. In Figure 3b we report a bar plot with the average slope values obtained for both sets. In particular, we observe a weak time dependence (B = 0.11–0.16) for the LUMO-pinning case in the side indentation. It should be noted that the slope increases with the value of the reorganization energy assigned to HIS35 (see SI).

We now turn to comparing the hopping I(V) curves with those obtained for a fully coherent transport (in the spirit of the Landauer formalism, Figure 4). For each method of contact formation, we considered three different MD frames for the three level-alignment situations.

Figure 4

Figure 4. One-site hopping and coherent-transport IV curves for three selected MD time frames of the blinking (a) and the lateral indentation (b) simulations in the HOMO-dominated, symmetric, and LUMO-dominated cases.

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In most cases, the current calculated for a hopping mechanism appears to be higher than the corresponding one obtained within a fully coherent transport. This is not the case, however, for the lateral indentation in the symmetric scheme, especially at a short tip–protein distance. In particular, we observe that the coherent-transport currents for the HOMO-dominated case are similar to those from their symmetric counterparts. This is because the HOMO resonance is extremely sharp (18) (as compared, for instance, to the LUMO resonance (21)). Overall, these results seem to suggest that within hopping through a single site, preference over one transport mechanism or the other may depend on both the specific gate-voltage applied and the geometrical position of the tip with respect to the protein.

Finally, we stress that one should not rule out the possibility of more hopping sites taking place in the transport process. Previous works of ours (22,37) highlighted the presence of several states lying below the HOMO and energetically very close to it. These states originate from moieties other than the Cu ion, and they are located all over the peripheral area of the protein structure. In order to obtain an approximate estimate of their possible contribution in electron transport, we built a model in which each hopping site comprises several of these residues. In Figure 5, we show the current curves for a time frame of the lateral-indentation simulation obtained for hopping through three sites in the symmetric scheme. More specifically, the first site includes the residues ASP11, HIS46, ASP93, GLU104, and GLU106, which are spatially located between the surface and Cu. The second hopping site is the Cu ion. The third site includes the residues ASP55, ASP69, ASP71, ASP76, CYS112, and HIS117, which are comprised between the Cu ion and the tip. These residues were chosen as they all contribute to states very close to the Fermi level (within a range of 0.2 eV). We have assigned two different reorganization energy λL and λR to the first and third site, respectively. It is possible to observe that regardless of the values of these two parameters, the current would be significantly higher than assuming hopping through the Cu ion only. We refer the reader to the SI for a more detailed analysis of the role of the number of hopping sites.

Figure 5

Figure 5. Comparison between the current obtained for one-site and three-site hopping for different values of the reorganization energies of the two sets of residues forming the first and third sites (λL and λR, respectively). These specific data were extracted from the lateral-indentation scheme for d = 2.54 nm.

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A quantitative comparison to experimental results is not straightforward. It would require a systematic study of experimental I(V)s as a function of the tip-to-surface gap separation. While this is experimentally reachable, this study implies a large block of experimental work and is beyond the scope of the current study. However, we observe that the current values reported in the literature for single-azurin experiments (around 1/2 nA (42)) would not be achieved in the symmetric scheme but rather in a situation in which one of the two frontier orbitals lies closer to the Fermi level.

In summary, we have studied electron transport through a metal–protein–metal junction based on a blue-copper azurin. By adopting a procedure based on fully quantum calculations, we have taken into account the whole atomic and electronic structure of the entire junction. We found that the asymmetry of the I(V) curves is strongly affected by the specific position of the tip in the junction. We also found that within a one-site hopping framework, hopping currents can be higher or lower than the coherent-transport currents depending on the energy alignment of the protein orbitals with respect to the Fermi level. Higher hopping currents can be obtained, however, by considering more than one stepping site. Finally, we addressed the very low temperature dependence of the conductance, which was previously observed in several experiments. We have shown that this hopping framework allows for such independence under certain conditions related to the energy alignment of the protein orbitals and to the reorganization energies of the hopping sites. To a certain extent, by showing that drastic changes can be induced in the transport mechanism by the various factors we have analyzed, our results provide an explanation for the presence of conflicting conclusions drawn in the previous literature. In view of the high complexity of these systems, we believe that our results provide guidance for the interpretation of the experimental results.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jpclett.3c02702.

  • Theoretical details for an N-site hopping model (S1); the role of the protein–electrode coupling in the asymmetry of the IV curves; (S2) dependency of hopping rates on the bias voltage (S3); dependency of hopping currents on reorganization-energy values (S4); and temperature dependence for different reorganization-energy values (S5) (PDF)

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Author Information

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  • Corresponding Author
    • Linda A. Zotti - Departamento de Física Teórica de la Materia Condensada, Universidad Autónoma de Madrid, E-28049 Madrid, Spain;  Condensed Matter Physics Center (IFIMAC), Universidad Autónoma de Madrid, E-28049 Madrid, Spain;  Orcidhttps://orcid.org/0000-0002-5292-6759;  Email: [email protected]
  • Authors
    • Carlos Roldán-Piñero - Departamento de Física Teórica de la Materia Condensada, Universidad Autónoma de Madrid, E-28049 Madrid, Spain
    • Carlos Romero-Muñiz - Departamento de Física de la Materia Condensada, Universidad de Sevilla, PO Box 1065, 41080 Sevilla, Spain;  Orcidhttps://orcid.org/0000-0001-6902-1553
    • Ismael Díez-Pérez - Department of Chemistry, Faculty of Natural & Mathematical Sciences, King’s College London, Britannia House, 7 Trinity Street, London SE1 1DB, U.K.;  Orcidhttps://orcid.org/0000-0003-0513-8888
    • J. G. Vilhena - Departamento de Física Teórica de la Materia Condensada, Universidad Autónoma de Madrid, E-28049 Madrid, Spain;  Condensed Matter Physics Center (IFIMAC), Universidad Autónoma de Madrid, E-28049 Madrid, Spain;  Orcidhttps://orcid.org/0000-0001-8338-9119
    • Rubén Pérez - Departamento de Física Teórica de la Materia Condensada, Universidad Autónoma de Madrid, E-28049 Madrid, Spain;  Condensed Matter Physics Center (IFIMAC), Universidad Autónoma de Madrid, E-28049 Madrid, Spain;  Orcidhttps://orcid.org/0000-0001-5896-541X
    • Juan Carlos Cuevas - Departamento de Física Teórica de la Materia Condensada, Universidad Autónoma de Madrid, E-28049 Madrid, Spain;  Condensed Matter Physics Center (IFIMAC), Universidad Autónoma de Madrid, E-28049 Madrid, Spain;  Orcidhttps://orcid.org/0000-0001-7421-0682
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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L.A.Z. is grateful for the financial support from MCIN/AEI/10.13039/501100011033 (Grant PID2021-125604NB-I00). C.R.P. and L.A.Z. acknowledge financial support from the Universidad Autónoma de Madrid/Comunidad de Madrid (Grant No. SI3/PJI/2021- 00191). J.C.C. acknowledges funding from the Spanish Ministry of Science and Innovation (PID2020-114880GB-I00). C.R.-M. acknowledges financial support by the Ramón y Cajal program of the Spanish Ministry of Science and Innovation (ref. RYC2021-031176-I). I.D.-P. thanks support from the European Research Council (ERC) under the European Union Horizon 2020 research and innovation program (Grant Agreement ERC Fields4CAT-772391) and from UKRI-BBSRC BB/X002810/1. J.G.V. acknowledges funding from the Spanish CM “Talento Program” (Project No. 2020-T1/ND-20306), and the Spanish Ministerio de Ciencia e Innovación (Grant Nos. PID2020-113722RJ-I00 and TED2021-132219A-I00). R.P. acknowledges support from the Ministerio de Ciencia e Innovación (MCIN) through the Project PID2020-115864RB-I00 and the “María de Maeztu” Programme for Units of Excellence in R&D (Grant No. CEX2018-000805-M). We thank Francesca Marchetti for fruitful discussions and Spiros Skourtis for help with the effective coupling methods.

References

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    A review. Biomol. electronics is a rapidly growing multidisciplinary field that combines biol., nanoscience, and engineering to bridge the two important fields of life sciences and mol. electronics. Proteins are remarkable for their ability to recognize mols. and transport electrons, making the integration of proteins into electronic devices a long sought-after goal and leading to the emergence of the field of protein-based bioelectronics, also known as proteotronics. This field seeks to design and create new biomol. electronic platforms that allow for the understanding and manipulation of protein-mediated electronic charge transport and related functional applications. In recent decades, there have been numerous reports on protein-based bioelectronics using a variety of nano-gapped elec. devices and techniques at the single mol. level, which are not achievable with conventional ensemble approaches. This review focuses on recent advances in phys. electron transport mechanisms, device fabrication methodologies, and various applications in protein-based bioelectronics. We discuss the most recent progress of the single or few protein-bridged elec. junction fabrication strategies, summarize the work on fundamental and functional applications of protein bioelectronics that enable high and dynamic electron transport, and highlight future perspectives and challenges that still need to be addressed. We believe that this specific review will stimulate the interdisciplinary research of topics related to protein-related bioelectronics, and open up new possibilities for single-mol. biophysics and biomedicine.
  2. 2
    Ha, T. Q.; Planje, I. J.; White, J. R. G.; Aragonès, A. C.; Díez-Pérez, I. Charge transport at the protein–electrode interface in the emerging field of BioMolecular Electronics. Curr. Opin. Electrochem. 2021, 28, 100734,  DOI: 10.1016/j.coelec.2021.100734
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    Charge transport at the protein-electrode interface in the emerging field of BioMolecular Electronics
    Ha, Tracy Q.; Planje, Inco J.; White, Jhanelle R. G.; Aragones, Albert C.; Diez-Perez, Ismael
    Current Opinion in Electrochemistry (2021), 28 (), 100734CODEN: COEUCY; ISSN:2451-9111. (Elsevier B.V.)
    A review. The first is to use nature's efficient charge transport mechanisms as an inspiration to build the next generation of hybrid bioelectronic devices towards a more sustainable, biocompatible and efficient technol. The second is to understand this ubiquitous physicochem. process in life, exploited in many fundamental biol. processes such as cell signalling, respiration, photosynthesis or enzymic catalysis, leading us to a better understanding of disease mechanisms connected to charge diffusion. Extg. elec. signatures from a protein requires optimized methods for tethering the mols. to an electrode surface, where it is advantageous to have precise electrochem. control over the energy levels of the hybrid protein-electrode interface. Here, we review recent progress towards understanding the charge transport mechanisms through protein-electrode-protein junctions, which has led to the rapid development of the new BioMol. Electronics field. The field has brought a new vision into the mol. electronics realm, wherein complex supramol. structures such as proteins can efficiently transport charge over long distances when placed in a hybrid bioelectronic device. Such anomalous long-range charge transport mechanisms acutely depend on specific chem. modifications of the supramol. protein structure and on the precisely engineered protein-electrode chem. interactions. Key areas to explore in more detail are parameters such as protein stiffness (dynamics) and intrinsic electrostatic charge and how these influence the transport pathways and mechanisms in such hybrid devices.
  3. 3
    Krishnan, S.; Aksimentiev, A.; Lindsay, S.; Matyushov, D. Long-Range Conductivity in Proteins Mediated by Aromatic Residues. ACS Phys. Chem. Au 2023, 3, 444,  DOI: 10.1021/acsphyschemau.3c00017
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    Long-Range Conductivity in Proteins Mediated by Aromatic Residues
    Krishnan, Siddharth; Aksimentiev, Aleksei; Lindsay, Stuart; Matyushov, Dmitry
    ACS Physical Chemistry Au (2023), 3 (5), 444-455CODEN: APCACH; ISSN:2694-2445. (American Chemical Society)
    Single-mols. measurements show that many proteins, lacking any redox cofactors, nonetheless exhibit elec. conductance on the order of a nanosiemen over 10 nm distances, implying that electrons can transit an entire protein in less than a nanosecond when subject to a p.d. of less than 1 V. This is puzzling because, for fast transport (i.e., a free energy barrier of zero), the hopping rate is detd. by the reorganization energy of approx. 0.8 eV, and this sets the time scale of a single hop to at least 1μs. Furthermore, the Fermi energies of typical metal electrodes are far removed from the energies required for sequential oxidn. and redn. of the arom. residues of the protein, which should further reduce the hopping current. Here, we combine all-atom mol. dynamics (MD) simulations of non-redox-active proteins (consensus tetratricopeptide repeats) with an electron transfer theory to demonstrate a mol. mechanism that can account for the unexpectedly fast electron transport. According to our MD simulations, the reorganization energy produced by the energy shift on charging (the Stokes shift) is close to the conventional value of 0.8 eV. However, the non-ergodic sampling of mol. configurations by the protein results in reaction-reorganization energies, extd. directly from the distribution of the electrostatic energy fluctuations, that are only ∼0.2 eV, which is small enough to enable long-range cond., without invoking quantum coherent transport. Using the MD values of the reorganization energies, we calc. a current decay with distance that is in agreement with expt.
  4. 4
    Bostick, C. D.; Mukhopadhyay, S.; Pecht, I.; Sheves, M.; Cahen, D.; Lederman, D. Protein Bioelectronics: A review of what we do and do not know. Rep. Prog. Phys. 2018, 81, 026601,  DOI: 10.1088/1361-6633/aa85f2
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    Protein bioelectronics: a review of what we do and do not know
    Bostick, Christopher D.; Mukhopadhyay, Sabyasachi; Pecht, Israel; Sheves, Mordechai; Cahen, David; Lederman, David
    Reports on Progress in Physics (2018), 81 (2), 026601/1-026601/57CODEN: RPPHAG; ISSN:1361-6633. (IOP Publishing Ltd.)
    A review. We review the status of protein-based mol. electronics. First, we define and discuss fundamental concepts of electron transfer and transport in and across proteins and proposed mechanisms for these processes. We then describe the immobilization of proteins to solid-state surfaces in both nanoscale and macroscopic approaches, and highlight how different methodologies can alter protein electronic properties. Because immobilizing proteins while retaining biol. activity is crucial to the successful development of bioelectronic devices, we discuss this process at length. We briefly discuss computational predictions and their connection to exptl. results. We then summarize how the biol. activity of immobilized proteins is beneficial for bioelectronic devices, and how conductance measurements can shed light on protein properties. Finally, we consider how the research to date could influence the development of future bioelectronic devices.
  5. 5
    Eleonora, A.; Reggiani, L.; Pousset, J. Proteotronics: Electronic devices based on proteins. Sensors 2015, 319, 3– 7,  DOI: 10.1007/978-3-319-09617-9_1
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    Qiu, X.; Chiechi, R. C. Printable logic circuits comprising self-assembled protein complexes. Nat. Commun. 2022, 13, 2312,  DOI: 10.1038/s41467-022-30038-8
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    Printable logic circuits comprising self-assembled protein complexes
    Qiu, Xinkai; Chiechi, Ryan C.
    Nature Communications (2022), 13 (1), 2312CODEN: NCAOBW; ISSN:2041-1723. (Nature Portfolio)
    This paper describes the fabrication of digital logic circuits comprising resistors and diodes made from protein complexes and wired together using printed liq. metal electrodes. These resistors and diodes exhibit temp.-independent charge-transport over a distance of approximatley 10 nm and require no encapsulation or special handling. The function of the protein complexes is detd. entirely by self-assembly. When induced to self-assembly into anisotropic monolayers, the collective action of the aligned dipole moments increases the elec. cond. of the ensemble in one direction and decreases it in the other. When induced to self-assemble into isotropic monolayers, the dipole moments are randomized and the elec. cond. is approx. equal in both directions. We demonstrate the robustness and utility of these all-protein logic circuits by constructing pulse modulators based on AND and OR logic gates that function nearly identically to simulated circuits. These show that digital circuits with useful functionality can be derived from readily obtainable biomols. using simple, straightforward fabrication techniques that exploit mol. self-assembly, realizing one of the primary goals of mol. electronics.
  7. 7
    Artés, J. M.; Díez-Pérez, I.; Sanz, F.; Gorostiza, P. Direct measurement of electron transfer distance decay constants of single redox proteins by electrochemical tunneling spectroscopy. ACS Nano 2011, 5, 2060– 2066,  DOI: 10.1021/nn103236e
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    Direct Measurement of Electron Transfer Distance Decay Constants of Single Redox Proteins by Electrochemical Tunneling Spectroscopy
    Artes, Juan M.; Diez-Perez, Ismael; Sanz, Fausto; Gorostiza, Pau
    ACS Nano (2011), 5 (3), 2060-2066CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    We present a method to measure directly and at the single-mol. level the distance decay const. that characterizes the rate of electron transfer (ET) in redox proteins. Using an electrochem. tunneling microscope under bipotentiostatic control, we obtained current-distance spectroscopic recordings of individual redox proteins confined within a nanometric tunneling gap at a well-defined mol. orientation. The tunneling current decays exponentially, and the corresponding decay const. (β) strongly supports a two-step tunneling ET mechanism. Statistical anal. of decay const. measurements reveals differences between the reduced and oxidized states that may be relevant to the control of ET rates in enzymes and biol. electron transport chains.
  8. 8
    Ing, N. L.; El-Naggar, M. Y.; Hochbaum, A. I. Going the distance: Long-range conductivity in protein and peptide bioelectronic materials. J. Phys. Chem. B 2018, 122, 10403– 10423,  DOI: 10.1021/acs.jpcb.8b07431
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    Going the Distance: Long-Range Conductivity in Protein and Peptide Bioelectronic Materials
    Ing, Nicole L.; El-Naggar, Mohamed Y.; Hochbaum, Allon I.
    Journal of Physical Chemistry B (2018), 122 (46), 10403-10423CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    A review. Bioelectronic materials interface biomols., cells, organs, or organisms with electronic devices, and they represent an active and growing field of materials research. Protein and peptide nanostructures are ideal bioelectronic materials. They possess many of the properties required for biocompatibility across scales from enzymic to organismal interfaces, and recent examples of supramol. protein and peptide nanostructures exhibit impressive electronic properties. The ability of such natural and synthetic protein and peptide materials to conduct electricity over micrometer to centimeter length scales, however, is not readily understood from a conventional view of their amino acid building blocks. Distinct in structure and properties from solid-state inorg. and synthetic org. metals and semiconductors, supramol. conductive proteins and peptides require careful theor. treatment and exptl. characterization methods to understand their electronic structure. In this review, we discuss theory and exptl. evidence from recent literature describing the long-range conduction of electronic charge in protein and peptide materials. Electron transfer across proteins has been studied extensively, but application of models for such short-range charge transport to longer distances relevant to bioelectronic materials are less well-understood. Implementation of electronic band structure and electron transfer formulations in extended biomol. systems will be covered in the context of recent materials discoveries and efforts at characterization of electronic transport mechanisms.
  9. 9
    Romero-Muñiz, C.; Vilhena, J. G.; Pérez, R.; Cuevas, J. C.; Zotti, L. A. Recent advances in understanding the electron transport through metal-azurin-metal junctions. Front. Phys. 2022,  DOI: 10.3389/fphy.2022.950929
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    There is no corresponding record for this reference.
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    Sang, Y.; Mishra, S.; Tassinari, F.; Karuppannan, S. K.; Carmieli, R.; Teo, R. D.; Migliore, A.; Beratan, D. N.; Gray, H. B.; Pecht, I. Temperature dependence of charge and spin transfer in azurin. J. Phys. Chem. C 2021, 125, 9875– 9883,  DOI: 10.1021/acs.jpcc.1c01218
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    10
    Temperature Dependence of Charge and Spin Transfer in Azurin
    Sang, Yutao; Mishra, Suryakant; Tassinari, Francesco; Kumar, Karuppannan S.; Carmieli, Raanan; Teo, Ruijie D.; Migliore, Agostino; Beratan, David N.; Gray, Harry B.; Pecht, Israel; Fransson, Jonas; Waldeck, David H.; Naaman, Ron
    Journal of Physical Chemistry C (2021), 125 (18), 9875-9883CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    The steady-state charge and spin transfer yields were measured for three different Ru-modified azurin derivs. in protein films on silver electrodes. While the charge-transfer yields exhibit weak temp. dependences, consistent with operation of a near activation-less mechanism, the spin selectivity of the electron transfer improves as temp. increases. This enhancement of spin selectivity with temp. is explained by a vibrationally induced spin exchange interaction between the Cu(II) and its chiral ligands. Distinct mechanisms control charge and spin transfer within proteins. As with electron charge transfer, proteins deliver polarized electron spins with a yield that depends on the protein's structure. This finding suggests a new role for protein structure in biochem. redox processes.
  11. 11
    Ortega, M.; Vilhena, J. G.; Zotti, L. A.; Díez-Pérez, I.; Cuevas, J. C.; Pérez, R. Tuning structure and dynamics of blue copper azurin junctions via single amino-acid mutations. Biomolecules 2019, 9, 611,  DOI: 10.3390/biom9100611
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    11
    Tuning structure and dynamics of blue copper azurin junctions via single amino-acid mutations
    Ortega, Maria; Vilhena, J. G.; Zotti, Linda A.; Diez-Perez, Ismael; Cuevas, Juan Carlos; Perez, Ruben
    Biomolecules (2019), 9 (10), 611CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)
    Here we address this issue using all-atom Mol. Dynamics (MD) of Pseudomonas Aeruginosa Azurin adsorbed to a Au(111) substrate. In particular, we focus on the structure and dynamics of the free/adsorbed protein and how these properties are altered upon single-point mutations. The results revealed that wild-type Azurin adsorbs on Au(111) along two well defined configurations: one tethered via cysteine groups and the other via the hydrophobic pocket surrounding the Cu2+. Surprisingly, our simulations revealed that single amino-acid mutations gave rise to a quenching of protein vibrations ultimately resulting in its overall stiffening. Given the role of amino-acid vibrations and reorientation in the dehydration process at the protein-water-substrate interface, we suggest that this might have an effect on the adsorption process of the mutant, giving rise to new adsorption configurations.
  12. 12
    Kayser, B.; Fereiro, J. A.; Bhattacharyya, R.; Cohen, S. R.; Vilan, A.; Pecht, I.; Sheves, M.; Cahen, D. Solid-State Electron Transport via the Protein Azurin is Temperature-Independent Down to 4 K. J. Phys. Chem. Lett. 2020, 11, 144– 151,  DOI: 10.1021/acs.jpclett.9b03120
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    12
    Solid-state electron transport via the protein azurin is temperature-independent down to 4 K
    Kayser, Ben; Fereiro, Jerry A.; Bhattacharyya, Rajarshi; Cohen, Sidney R.; Vilan, Ayelet; Pecht, Israel; Sheves, Mordechai; Cahen, David
    Journal of Physical Chemistry Letters (2020), 11 (1), 144-151CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)
    Solid-state electronic transport (ETp) via the electron-transfer copper protein azurin (Az) was measured in Au/Az/Au junction configurations down to 4 K, the lowest temp. for solid-state protein-based junctions. Not only does lowering the temp. help when observing fine features of electronic transport, but it also limits possible electron transport mechanisms. Practically, wire-bonded devices-on-chip, carrying Az-based microscopic junctions, were measured in liq. He, minimizing temp. gradients across the samples. Much smaller junctions, in conducting-probe at. force microscopy measurements, served, between room temp. and the protein's denaturation temp. (∼323 K), to check that conductance behavior is independent of device configuration or contact nature and thus is a property of the protein itself. Temp.-independent currents were obsd. from ∼320 to 4 K. The exptl. results were fitted to a single-level Landauer model to ext. effective energy barrier and electrode-mol. coupling strength values and to compare data sets. Our results strongly support that quantum tunneling, rather than hopping, dominates ETp via Az.
  13. 13
    Artés, J. M.; López-Martínez, M.; Díez-Pérez, I.; Sanz, F.; Gorostiza, P. Conductance switching in single wired redox proteins. Small 2014, 10, 2537– 2541,  DOI: 10.1002/smll.201303753
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    Conductance Switching in Single Wired Redox Proteins
    Artes, Juan M.; Lopez-Martinez, Montserrat; Diez-Perez, Ismael; Sanz, Fausto; Gorostiza, Pau
    Small (2014), 10 (13), 2537-2541CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)
    We report the observation of switching evens in spontaneously formed single wire protein junctions in an electrochem. environment.
  14. 14
    Ruiz, M. P.; Aragonès, A. C.; Camarero, N.; Vilhena, J. G.; Ortega, M.; Zotti, L. A.; Pérez, R.; Cuevas, J. C.; Gorostiza, P.; Díez-Pérez, I. Bioengineering a single-protein junction. J. Am. Chem. Soc. 2017, 139, 15337– 15346,  DOI: 10.1021/jacs.7b06130
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    14
    Bioengineering a Single-Protein Junction
    Ruiz, Marta P.; Aragones, Albert C.; Camarero, Nuria; Vilhena, J. G.; Ortega, Maria; Zotti, Linda A.; Perez, Ruben; Cuevas, Juan Carlos; Gorostiza, Pau; Diez-Perez, Ismael
    Journal of the American Chemical Society (2017), 139 (43), 15337-15346CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Bioelectronics moves toward designing nanoscale electronic platforms that allow in vivo detns. Such devices require interfacing complex biomol. moieties as the sensing units to an electronic platform for signal transduction. Inevitably, a systematic design goes through a bottom-up understanding of the structurally related elec. signatures of the biomol. circuit, which will ultimately lead researchers to tailor its elec. properties. Toward this aim, the authors show here the first example of bioengineered charge transport in a single-protein elec. contact. A single point-site mutation at the docking hydrophobic patch of a Cu-azurin causes minor structural distortion of the protein blue Cu site and a dramatic change in the charge transport regime of the single-protein contact, which goes from the classical Cu-mediated two-step transport in this system to a direct coherent tunneling. The authors' extensive spectroscopic studies and mol.-dynamics simulations show that the proteins' folding structures are preserved in the single-protein junction. The DFT-computed frontier orbital of the relevant protein segments suggests that the Cu center participation in each protein variant accounts for the different obsd. charge transport behavior. This work is a direct evidence of charge transport control in a protein backbone through external mutagenesis and a unique nanoscale platform to study structurally related biol. electron transfer.
  15. 15
    Valianti, S.; Cuevas, J. C.; Skourtis, S. S. Charge-transport mechanisms in azurin-based monolayer junctions. J. Phys. Chem. C 2019, 123, 5907– 5922,  DOI: 10.1021/acs.jpcc.9b00135
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    Charge-Transport Mechanisms in Azurin-Based Monolayer Junctions
    Valianti, Stephanie; Cuevas, Juan-Carlos; Skourtis, Spiros S.
    Journal of Physical Chemistry C (2019), 123 (10), 5907-5922CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    We study the transport mechanisms of different types of azurin (Az) monolayer heterojunctions with a variety of metal substituents. The systems include Holo-Az (Cu-substituted), Apo-Az (no metal), and Ni-, Co- and Zn-substituted azurins. Our theor. anal. is based on measurements of the voltage and temp. dependencies of the current and attempts to reproduce both dependencies using a common mechanism and corresponding set of parameters. Our results strongly suggest that for Holo-Az the transport mechanism depends on the protein monolayer/heterojunction setup. In one type of heterojunction, transport is dominated by resonant incoherent hopping through the Cu redox site, whereas in the other it is mediated by off-resonant tunneling. For the unsubstituted (Apo-Az) and other metal-substituted azurins, the dominant transport mechanism at low temps. is off-resonant tunneling, with an av. tunneling barrier that depends on the type of metal dopant, and at the highest temps., it is through-amino-acid hopping. Our modeling results are relevant to the anal. of the current behavior over a range of temps. for any mol. heterojunction device.
  16. 16
    Amdursky, N.; Marchak, D.; Sepunaru, L.; Pecht, I.; Sheves, M.; Cahen, D. Electronic transport via proteins. Adv. Mater. 2014, 26, 7142– 7161,  DOI: 10.1002/adma.201402304
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    Electronic Transport via Proteins
    Amdursky, Nadav; Marchak, Debora; Sepunaru, Lior; Pecht, Israel; Sheves, Mordechai; Cahen, David
    Advanced Materials (Weinheim, Germany) (2014), 26 (42), 7142-7161CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. A central vision in mol. electronics is the creation of devices with functional mol. components that may provide unique properties. Proteins are attractive candidates for this purpose, as they have specific phys. (optical, elec.) and chem. (selective binding, self-assembly) functions and offer a myriad of possibilities for (bio-)chem. modification. This Progress Report focuses on proteins as potential building components for future bioelectronic devices as they are quite efficient electronic conductors, compared with satd. org. mols. The report addresses several questions: how general is this behavior; how does protein conduction compare with that of satd. and conjugated mols.; and what mechanisms enable efficient conduction across these large mols. To answer these questions results of nanometer-scale and macroscopic electronic transport measurements across a range of org. mols. and proteins are compiled and analyzed, from single/few mols. to large mol. ensembles, and the influence of measurement methods on the results is considered. Generalizing, it is found that proteins conduct better than satd. mols., and somewhat poorer than conjugated mols. Significantly, the presence of cofactors (redox-active or conjugated) in the protein enhances their conduction, but without an obvious advantage for natural electron transfer proteins. Most likely, the conduction mechanisms are hopping (at higher temps.) and tunneling (below ca. 150-200 K).
  17. 17
    Artés, J. M.; Díez-Pérez, I.; Gorostiza, P. Transistor-like behavior of single metalloprotein junctions. Nano Lett. 2012, 12, 2679– 2684,  DOI: 10.1021/nl2028969
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    Transistor-like Behavior of Single Metalloprotein Junctions
    Artes, Juan M.; Diez-Perez, Ismael; Gorostiza, Pau
    Nano Letters (2012), 12 (6), 2679-2684CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
    Single protein junctions consisting of azurin bridged between a gold substrate and the probe of an electrochem. tunneling microscope (ECSTM) were obtained by two independent methods that allowed statistical anal. over a large no. of measured junctions. Conductance measurements yield (7.3 ± 1.5) × 10-6G0 in agreement with reported ests. using other techniques. Redox gating of the protein with an on/off ratio of 20 was demonstrated and constitutes a proof-of-principle of a single redox protein field-effect transistor.
  18. 18
    Romero-Muñiz, C.; Ortega, M.; Vilhena, J. G.; Díez-Pérez, I.; Pérez, R.; Cuevas, J. C.; Zotti, L. A. Can. electron transport through a blue-copper azurin be coherent? An ab initio study. J. Phys. Chem. C 2021, 125, 1693– 1702,  DOI: 10.1021/acs.jpcc.0c09364
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    18
    Can Electron Transport through a Blue-Copper Azurin Be Coherent? An Ab Initio Study
    Romero-Muniz, Carlos; Ortega, Maria; Vilhena, J. G.; Diez-Perez, Ismael; Perez, Ruben; Cuevas, Juan Carlos; Zotti, Linda A.
    Journal of Physical Chemistry C (2021), 125 (3), 1693-1702CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    Multiple expts. on the electron transport through solid-state junctions based on different proteins suggested that the dominant transport mechanism is quantum tunneling (or coherent transport). This is extremely surprising given the length of these mols. (2-7 nm) and their electronic structure (mainly comprising very localized MOs). Overall, this is probably the single most important puzzle in the field of biomol. electronics and calls for rigorous calcns. of the tunneling probability in protein-based junctions. Motivated by these expts., the authors tackle here this problem and report a comprehensive theor. study of the coherent electron transport in metal-protein-metal junctions based on the blue-copper azurin from Pseudomonas aeruginosa, which is the workhorse in protein electronics. More precisely, the authors focus on single-mol. junctions realized in STM-based expts. and analyze a wide variety of contact scenarios. The authors' calcns. are based on a combination of mol. dynamics simulations and ab initio transport calcns. The authors' results unambiguously show that when azurin is not deformed and retains its pristine structure, the end-to-end tunneling probability is exceedingly small and does not give rise to any measurable elec. current. However, much higher tunneling probabilities are possible when either the STM tip (indented from the top) substantially compresses the protein or the protein is contacted sideways, significantly reducing the effective junction length. Also in certain configurations, the presence of surrounding water can also increase the conductance but it cannot explain the high conductance values reported exptl. In all cases, the current is found to flow through the Cu atom of this metalloprotein, although the role of several other levels close to the Fermi energy cannot be ruled out. The authors remark that the authors only evaluate the efficiency of coherent transport and the anal. of the relevance of other potential charge-transport mechanisms is out of the scope of the authors' work.
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    Yu, X.; Lovrincic, R.; Sepunaru, L.; Li, W.; Vilan, A.; Pecht, I.; Sheves, M.; Cahen, D. Insights into solid-state electron transport through proteins from inelastic tunneling spectroscopy: The case of azurin. ACS Nano 2015, 9, 9955– 9963,  DOI: 10.1021/acsnano.5b03950
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    19
    Insights into Solid-State Electron Transport through Proteins from Inelastic Tunneling Spectroscopy: The Case of Azurin
    Yu, Xi; Lovrincic, Robert; Sepunaru, Lior; Li, Wenjie; Vilan, Ayelet; Pecht, Israel; Sheves, Mordechai; Cahen, David
    ACS Nano (2015), 9 (10), 9955-9963CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Surprisingly efficient solid-state electron transport has recently been demonstrated through "dry" proteins (with only structural, tightly bound H2O left), suggesting proteins as promising candidates for mol. (bio)electronics. Using inelastic electron tunneling spectroscopy (IETS), we explored electron-phonon interaction in metal/protein/metal junctions, to help understand solid-state electronic transport across the redox protein azurin. To that end an oriented azurin monolayer on Au is contacted by soft Au electrodes. Characteristic vibrational modes of amide and amino acid side groups as well as of the azurin-electrode contact were obsd., revealing the azurin native conformation in the junction and the crit. role of side groups in the charge transport. The lack of abrupt changes in the conductance and the line shape of IETS point to far off-resonance tunneling as the dominant transport mechanism across azurin, in line with previously reported (and herein confirmed) azurin junctions. The inelastic current and hence electron-phonon interaction appear to be rather weak and comparable in magnitude with the inelastic fraction of tunneling current via alkyl chains, which may reflect the known structural rigidity of azurin.
  20. 20
    Papp, E.; Vattay, G.; Romero-Muñiz, C.; Zotti, L. A.; Fereiro, J. A.; Sheves, M.; Cahen, D. Experimental data confirm carrier-cascade model for solid-state conductance across proteins. J. Phys. Chem. B 2023, 127, 1728– 1734,  DOI: 10.1021/acs.jpcb.2c07946
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    Experimental Data Confirm Carrier-Cascade Model for Solid-State Conductance across Proteins
    Papp, Eszter; Vattay, Gabor; Romero-Muniz, Carlos; Zotti, Linda A.; Fereiro, Jerry A.; Sheves, Mordechai; Cahen, David
    Journal of Physical Chemistry B (2023), 127 (8), 1728-1734CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    The finding that electronic conductance across ultrathin protein films between metallic electrodes remains nearly const. from room temp. to just a few K has posed a challenge. We show that a model based on a generalized Landauer formula explains the nearly const. conductance and predicts an Arrhenius-like dependence for low temps. A crit. aspect of the model is that the relevant activation energy for conductance is either the difference between the HOMO and HOMO-1 or the LUMO+1 and LUMO energies instead of the HOMO-LUMO gap of the proteins. Anal. of exptl. data confirms the Arrhenius-like law and allows us to ext. the activation energies. We then calc. the energy differences with advanced DFT methods for proteins used in the expts. Our main result is that the exptl. and theor. activation energies for these three different proteins and three differently prepd. solid-state junctions match nearly perfectly, implying the mechanism's validity.
  21. 21
    Romero-Muñiz, C.; Ortega, M.; Vilhena, J. G.; Pérez, R.; Cuevas, J. C.; Zotti, L. A. The role of metal ions in the electron transport through azurin-based junctions. Appl. Sci. 2021, 11, 3732,  DOI: 10.3390/app11093732
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    The role of metal ions in the electron transport through azurin-based junctions
    Romero-Muniz, Carlos; Ortega, Maria; Vilhena, Jose Guilherme; Perez, Ruben; Cuevas, Juan Carlos; Zotti, Linda A.
    Applied Sciences (2021), 11 (9), 3732CODEN: ASPCC7; ISSN:2076-3417. (MDPI AG)
    We studied the coherent electron transport through metal-protein-metal junctions based on a blue copper azurin, in which the copper ion was replaced by three different metal ions (Co, Ni and Zn). Our results show that neither the protein structure nor the transmission at the Fermi level change significantly upon metal replacement. The discrepancy with previous exptl. observations suggests that the transport mechanism taking place in these types of junctions is probably not fully coherent.
  22. 22
    Romero-Muñiz, C.; Ortega, M.; Vilhena, J. G.; Diéz-Pérez, I.; Cuevas, J. C.; Pérez, R.; Zotti, L. A. Mechanical deformation and electronic structure of a blue copper azurin in a solid-state junction. Biomolecules 2019, 9, 506,  DOI: 10.3390/biom9090506
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    Mechanical deformation and electronic structure of a blue copper azurin in a solid-state junction
    Romero-Muniz, Carlos; Ortega, Maria; Vilhena, J. G.; Diez-Perez, Ismael; Cuevas, Juan Carlos; Perez, Ruben; Zotti, Linda A.
    Biomolecules (2019), 9 (9), 506CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)
    Protein-based electronics is an emerging field which has attracted considerable attention over the past decade. Here, we present a theor. study of the formation and electronic structure of a metal-protein-metal junction based on the blue-copper azurin from pseudomonas aeruginosa. We focus on the case in which the protein is adsorbed on a gold surface and is contacted, at the opposite side, to an STM (Scanning Tunneling Microscopy) tip by spontaneous attachment. This has been simulated through a combination of mol. dynamics and d. functional theory. We find that the attachment to the tip induces structural changes in the protein which, however, do not affect the overall electronic properties of the protein. Indeed, only changes in certain residues are obsd., whereas the electronic structure of the Cu-centered complex remains unaltered, as does the total d. of states of the whole protein.
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    Ozaki, T. Variationally optimized atomic orbitals for large-scale electronic structures. Phys. Rev. B 2003, 67, 155108,  DOI: 10.1103/PhysRevB.67.155108
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    Variationally optimized atomic orbitals for large-scale electronic structures
    Ozaki, T.
    Physical Review B: Condensed Matter and Materials Physics (2003), 67 (15), 155108/1-155108/5CODEN: PRBMDO; ISSN:0163-1829. (American Physical Society)
    A simple and practical method for variationally optimizing numerical AOs used in d. functional calcns. is presented based on the force theorem. The derived equation provides the same procedure for the optimization of AOs as that for the geometry optimization. The optimized orbitals well reproduce convergent results calcd. by a larger no. of unoptimized orbitals. In addn., we demonstrate that the optimized orbitals significantly reduce the computational effort in the geometry optimization, while keeping a high degree of accuracy.
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    Ozaki, T.; Kino, H. Numerical atomic basis orbitals from H to Kr. Phys. Rev. B 2004, 69, 195113,  DOI: 10.1103/PhysRevB.69.195113
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    Numerical atomic basis orbitals from H to Kr
    Ozaki, T.; Kino, H.
    Physical Review B: Condensed Matter and Materials Physics (2004), 69 (19), 195113/1-195113/19CODEN: PRBMDO; ISSN:0163-1829. (American Physical Society)
    We present a systematic study for numerical at. basis orbitals ranging from H to Kr, which could be used in large scale O(N) electronic structure calcns. based on d.-functional theories (DFT). The comprehensive investigation of convergence properties with respect to our primitive basis orbitals provides a practical guideline in an optimum choice of basis sets for each element, which well balances the computational efficiency and accuracy. Moreover, starting from the primitive basis orbitals, a simple and practical method for variationally optimizing basis orbitals is presented based on the force theorem, which enables us to maximize both the computational efficiency and accuracy. The optimized orbitals well reproduce convergent results calcd. by a larger no. of primitive orbitals. As illustrations of the orbital optimization, we demonstrate two examples: the geometry optimization coupled with the orbital optimization of a C60 mol. and the preorbital optimization for a specific group such as proteins. They clearly show that the optimized orbitals significantly reduce the computational efforts, while keeping a high degree of accuracy, thus indicating that the optimized orbitals are quite suitable for large scale DFT calcns.
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    Amdursky, N.; Sepunaru, L.; Raichlin, S.; Pecht, I.; Sheves, M.; Cahen, D. Electron transfer proteins as electronic conductors: Significance of the metal and its binding site in the blue Cu protein, azurin. Adv. Sci. 2015, 2, 1400026,  DOI: 10.1002/advs.201400026
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    Electron Transfer Proteins as Electronic Conductors: Significance of the Metal and Its Binding Site in the Blue Cu Protein, Azurin
    Amdursky Nadav; Raichlin Sara; Sepunaru Lior; Cahen David; Pecht Israel; Sheves Mordechai
    Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2015), 2 (4), 1400026 ISSN:2198-3844.
    Electron transfer (ET) proteins are biomolecules with specific functions, selected by evolution. As such they are attractive candidates for use in potential bioelectronic devices. The blue copper protein azurin (Az) is one of the most-studied ET proteins. Traditional spectroscopic, electrochemical, and kinetic methods employed for studying ET to/from the protein's Cu ion have been complemented more recently by studies of electrical conduction through a monolayer of Az in the solid-state, sandwiched between electrodes. As the latter type of measurement does not require involvement of a redox process, it also allows monitoring electronic transport (ETp) via redox-inactive Az-derivatives. Here, results of macroscopic ETp via redox-active and -inactive Az derivatives, i.e., Cu(II) and Cu(I)-Az, apo-Az, Co(II)-Az, Ni(II)-Az, and Zn(II)-Az are reported and compared. It is found that earlier reported temperature independence of ETp via Cu(II)-Az (from 20 K until denaturation) is unique, as ETp via all other derivatives is thermally activated at temperatures >≈200 K. Conduction via Cu(I)-Az shows unexpected temperature dependence >≈200 K, with currents decreasing at positive and increasing at negative bias. Taking all the data together we find a clear compensation effect of Az conduction around the Az denaturation temperature. This compensation can be understood by viewing the Az binding site as an electron trap, unless occupied by Cu(II), as in the native protein, with conduction of the native protein setting the upper transport efficiency limit.
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    Cuevas, J. C.; Scheer, E. Molecular electronics: An introduction to theory and experiment; World Scientific: 2017.
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    Valianti, S.; Skourtis, S. S. Observing donor-to-acceptor electron-transfer rates and the Marcus inverted parabola in Molecular Junctions. J. Phys. Chem. B 2019, 123, 9641– 9653,  DOI: 10.1021/acs.jpcb.9b07371
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    Observing Donor-to-Acceptor Electron-Transfer Rates and the Marcus Inverted Parabola in Molecular Junctions
    Valianti, Stephanie; Skourtis, Spiros S.
    Journal of Physical Chemistry B (2019), 123 (45), 9641-9653CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    A recurring theme in mol. electronics is the relationship between the intramol. electron transfer rate in a donor-bridge-acceptor system and the conductance at low bias in the corresponding electrode-bridge-electrode junction. The similarities between through-bridge donor-to-acceptor electron tunneling and through-bridge electrode-to-electrode Landauer transport led to the suggestion of an approx. linear relationship between the rate and the conductance for any given bridge. A large body of work indicates that the two quantities are not necessarily linearly related, showing different behaviors as a function of temp., voltage and bridge length. Apart from Landauer tunneling, incoherent hopping can be an important mechanism in mol. junctions. We propose a donor-bridge-acceptor mol. junction, functioning in the incoherent hopping regime, that is suited for establishing direct correlations between the electrode-to-electrode current and the intramol. donor-to-acceptor electron transfer rate. We suggest that this type of junction may be used to observe the Marcus-inverted-parabola dependence of the intramol. rate on energy gap by varying the bias voltage. The realization of such an expt. would enable meaningful comparisons between soln.-phase electron transfer rates and mol.-junction currents for the same mol.
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    Migliore, A.; Nitzan, A. Nonlinear charge transport in redox molecular junctions: A Marcus perspective. ACS Nano 2011, 5, 6669– 6685,  DOI: 10.1021/nn202206e
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    Nonlinear Charge Transport in Redox Molecular Junctions: A Marcus Perspective
    Migliore, Agostino; Nitzan, Abraham
    ACS Nano (2011), 5 (8), 6669-6685CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Redox mol. junctions are mol. conduction junctions that involve more than one oxidn. state of the mol. bridge. This property is derived from the ability of the mol. to transiently localize transmitting electrons, implying relatively weak mol.-leads coupling and, in many cases, the validity of the Marcus theory of electron transfer. Here the authors study the implications of this property on the nonlinear transport properties of such junctions. The authors obtain an anal. soln. of the integral equations that describe mol. conduction in the Marcus kinetic regime and use it in different phys. limits to predict some important features of nonlinear transport in metal-mol.-metal junctions. In particular, conduction, rectification, and neg. differential resistance can be obtained in different regimes of interplay between two different conduction channels assocd. with different localization properties of the excess mol. charge, without specific assumptions about the electronic structure of the mol. bridge. The predicted behaviors show temp. dependences typically obsd. in the expt. The validity of the proposed model and ways to test its predictions and implement the implied control strategies are discussed.
  29. 29
    Markussen, T.; Jin, C.; Thygesen, K. S. Quantitatively accurate calculations of conductance and thermopower of molecular junctions. Phys. Status Solidi (b) 2013, 250, 2394– 2402,  DOI: 10.1002/pssb.201349217
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    Quantitatively accurate calculations of conductance and thermopower of molecular junctions
    Markussen, Troels; Jin, Chengjun; Thygesen, Kristian S.
    Physica Status Solidi B: Basic Solid State Physics (2013), 250 (11), 2394-2402CODEN: PSSBBD; ISSN:0370-1972. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Thermopower measurements of mol. junctions have recently gained interest as a characterization technique that supplements the more traditional conductance measurements. Here we investigate the electronic conductance and thermopower of benzenediamine (BDA) and benzenedicarbonitrile (BDCN) connected to gold electrodes using first-principles calcns. We find excellent agreement with expts. for both mols. when exchange-correlation effects are described by the many-body GW approxn. In contrast, results from std. d. functional theory (DFT) deviate from expts. by up to two orders of magnitude. The failure of DFT is particularly pronounced for the n-type BDCN junction due to the severe underestimation of the LUMO (LUMO). The quality of the DFT results can be improved by correcting the mol. energy levels for self-interaction errors and image charge effects. Finally, we show that the conductance and thermopower of the considered junctions are relatively insensitive to the metal-mol. bonding geometry. Our results demonstrate that electronic and thermoelec. properties of mol. junctions can be predicted from first-principles calcns. when exchange-correlation effects are taken properly into account.
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    Haiss, W.; Nichols, R. J.; van Zalinge, H.; Higgins, S. J.; Bethell, D.; Schiffrin, D. J. Measurement of single molecule conductivity using the spontaneous formation of molecular wires. Phys. Chem. Chem. Phys. 2004, 6, 4330– 4337,  DOI: 10.1039/b404929b
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    Measurement of single molecule conductivity using the spontaneous formation of molecular wires
    Haiss, Wolfgang; Nichols, Richard J.; van Zalinge, Harm; Higgins, Simon J.; Bethell, Donald; Schiffrin, David J.
    Physical Chemistry Chemical Physics (2004), 6 (17), 4330-4337CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
    A technique to measure the elec. cond. of single mols. was demonstrated. The method is based on trapping mols. between an STM tip and a substrate. The spontaneous attachment and detachment of α,ω-alkanedithiol mol. wires was easily monitored in the time domain. Elec. contact between the target mol. and the gold probes was achieved using thiol groups present at each end of the mol. Characteristic jumps in the tunnelling current were obsd. when the tip was positioned at a const. height and the STM feedback loop was disabled. Histograms of the measured current jump values were used to calc. the mol. cond. as a function of bias and chain length. These measurements can be carried out in a variety of environments, including aq. electrolytes. The changes in cond. with chain length obtained are in agreement with previous results obtained using a conducting AFM and the origin of some discrepancies in the literature is analyzed.
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    Haiss, W.; Wang, C.; Grace, I.; Batsanov, A. S.; Schiffrin, D. J.; Higgins, S. J.; Bryce, M. R.; Lambert, C. J.; Nichols, R. J. Precision control of single-molecule electrical junctions. Nat. Mater. 2006, 5, 995– 1002,  DOI: 10.1038/nmat1781
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    Precision control of single-molecule electrical junctions
    Haiss, Wolfgang; Wang, Changsheng; Grace, Iain; Batsanov, Andrei S.; Schiffrin, David J.; Higgins, Simon J.; Bryce, Martin R.; Lambert, Colin J.; Nichols, Richard J.
    Nature Materials (2006), 5 (12), 995-1002CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
    There is much discussion of mols. as components for future electronic devices. However, the contacts, the local environment and the temp. can all affect their elec. properties. This sensitivity, particularly at the single-mol. level, may limit the use of mols. as active elec. components, and therefore it is important to design and evaluate mol. junctions with a robust and stable elec. response over a wide range of junction configurations and temps. Here we report an approach to monitor the elec. properties of single-mol. junctions, which involves precise control of the contact spacing and tilt angle of the mol. Comparison with ab initio transport calcns. shows that the tilt-angle dependence of the elec. conductance is a sensitive spectroscopic probe, providing information about the position of the Fermi energy. It is also shown that the elec. properties of flexible mols. are dependent on temp., whereas those of mols. designed for their rigidity are not.
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    Díez-Pérez, I.; Hihath, J.; Lee, Y.; Yu, L.; Adamska, L.; Kozhushner, M. A.; Oleynik, I. I.; Tao, N. Rectification and stability of a single molecular diode with controlled orientation. Nat. Chem. 2009, 1, 635,  DOI: 10.1038/nchem.392
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    Rectification and stability of a single molecular diode with controlled orientation
    Diez-Perez, Ismael; Hihath, Joshua; Lee, Youngu; Yu, Luping; Adamska, Lyudmyla; Kozhushner, Mortko A.; Oleynik, Ivan I.; Tao, Nongjian
    Nature Chemistry (2009), 1 (8), 635-641CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
    In the mol. electronics field it is highly desirable to engineer the structure of mols. to achieve specific functions. In particular, diode (or rectification) behavior in single mols. is an attractive device function. Here the authors study charge transport through sym. tetra-Ph and nonsym. diblock dipyrimidinyldiphenyl mols. covalently bound to two electrodes. The orientation of the diblock is controlled through a selective deprotection strategy, and a method in which the electrode-electrode distance is modulated unambiguously dets. the current-voltage characteristics of the single-mol. device. The diblock mol. exhibits pronounced rectification behavior compared with its homologous sym. block, with current flowing from the dipyrimidinyl to the di-Ph moieties. This behavior is interpreted in terms of localization of the wave function of the hole ground state at one end of the diblock under the applied field. At large forward current, the mol. diode becomes unstable and quantum point contacts between the electrodes form.
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    Aragonès, A. C.; Darwish, N.; Ciampi, S.; Sanz, F.; Gooding, J. J.; Díez-Pérez, I. Single-molecule electrical contacts on silicon electrodes under ambient conditions. Nat. Commun. 2017, 8, 15056,  DOI: 10.1038/ncomms15056
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    Single-molecule electrical contacts on silicon electrodes under ambient conditions
    Aragones, Albert C.; Darwish, Nadim; Ciampi, Simone; Sanz, Fausto; Gooding, J. Justin; Diez-Perez, Ismael
    Nature Communications (2017), 8 (), 15056CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
    The ultimate goal in mol. electronics is to use individual mols. as the active electronic component of a real-world sturdy device. For this concept to become reality, it will require the field of single-mol. electronics to shift towards the semiconducting platform of the current microelectronics industry. Here, we report silicon-based single-mol. contacts that are mech. and elec. stable under ambient conditions. The single-mol. contacts are prepd. on silicon electrodes using the scanning tunnelling microscopy break-junction approach using a top metallic probe. The mol. wires show remarkable current-voltage reproducibility, as compared to an open silicon/nano-gap/metal junction, with current rectification ratios exceeding 4,000 when a low-doped silicon is used. The extension of the single-mol. junction approach to a silicon substrate contributes to the next level of miniaturization of electronic components and it is anticipated it will pave the way to a new class of robust single-mol. circuits.
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    Baldacchini, C.; Kumar, V.; Bizzarri, A. R.; Cannistraro, S. Electron tunnelling through single azurin molecules can be on/off switched by voltage pulses. Appl. Phys. Lett. 2015, 106, 183701,  DOI: 10.1063/1.4919911
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    Electron tunnelling through single azurin molecules can be on/off switched by voltage pulses
    Baldacchini, Chiara; Kumar, Vivek; Bizzarri, Anna Rita; Cannistraro, Salvatore
    Applied Physics Letters (2015), 106 (18), 183701/1-183701/4CODEN: APPLAB; ISSN:0003-6951. (American Institute of Physics)
    Redox metalloproteins are emerging as promising candidates for future bio-optoelectronic and nano-biomemory devices, and the control of their electron transfer properties through external signals is still a crucial task. Here, a reversible on/off switching of the electron current tunneling through a single protein can be achieved in azurin protein mols. adsorbed on gold surfaces, by applying appropriate voltage pulses through a scanning tunneling microscope tip. The obsd. changes in the hybrid system tunneling properties are discussed in terms of long-sustained charging of the protein milieu. (c) 2015 American Institute of Physics.
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    Fereiro, J. A.; Bendikov, T.; Pecht, I.; Sheves, M.; Cahen, D. Protein binding and orientation matter: Bias-induced conductance switching in a mutated azurin junction. J. Am. Chem. Soc. 2020, 142, 19217– 19225,  DOI: 10.1021/jacs.0c08836
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    Protein Binding and Orientation Matter: Bias-Induced Conductance Switching in a Mutated Azurin Junction
    Fereiro, Jerry A.; Bendikov, Tatyana; Pecht, Israel; Sheves, Mordechai; Cahen, David
    Journal of the American Chemical Society (2020), 142 (45), 19217-19225CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Reversible, bias-induced switching of conductance via a blue copper protein azurin mutant, N42C Az, with a nearly 10-fold increase at |V| > 0.8 v than at lower bias. were obsd. No such switching is found for wild-type azurin, WT Az, up to |1.2 V|, beyond which irreversible changes occur. The N42C Az mutant will, when positioned between electrodes in a solid-state Au-protein-Au junction, have an orientation opposite that of WT Az with respect to the electrodes. Current(s) via both proteins are temp.-independent, consistent with quantum mech. tunneling as dominant transport mechanism. No noticeable difference is resolved between the two proteins in conductance and inelastic electron tunneling spectra at <|0.5 V| bias voltages. Switching behavior persists from 15 K up to room temp. The conductance peak is consistent with the system switching in and out of resonance with the changing bias. With further input from UV photoemission measurements on Au-protein systems, these striking differences in conductance are rationalized by having the location of the Cu(II) coordination sphere in the N42C Az mutant, proximal to the (larger) substrate-electrode, to which the protein is chem. bound, while for the WT Az that coordination sphere is closest to the other Au electrode, with which only phys. contact is made. The authors' results establish the key roles that a protein's orientation and binding nature to the electrodes play in detg. the electron transport tunnel barrier.
  36. 36
    Alessandrini, A.; Facci, P. Electron transfer in nanobiodevices. Eur. Polym. J. 2016, 83, 450– 466,  DOI: 10.1016/j.eurpolymj.2016.03.028
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    Electron transfer in nanobiodevices
    Alessandrini, Andrea; Facci, Paolo
    European Polymer Journal (2016), 83 (), 450-466CODEN: EUPJAG; ISSN:0014-3057. (Elsevier Ltd.)
    A review. The present tutorial is aimed at introducing the reader to the main aspects of electron transfer in nanobiodevices. Nanobiodevices are faced both from scientific and technol. viewpoints and their particular implementation as electron transfer devices provides the opportunity of presenting fundamentals of electron transfer theory. Examples of implementations of stand alone devices, along with those involving reconfigurable set-ups based on an electrochem. scanning tunneling microscope, enable introducing heterogeneous electron transfer and electron transport theories in electrochem. environment. Specific cases of nanobiodevices involving redox metalloproteins are reported and exptl. results are interpreted and discussed in view of the most recent theor. advancements, in order to provide the reader with a comprehensive view of the results and promises in this exciting branch of nanotechnol.
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    Romero-Muñiz, C.; Ortega, M.; Vilhena, J. G.; Díez-Pérez, I.; Cuevas, J. C.; Pérez, R.; Zotti, L. A. Ab initio electronic structure calculations of entire blue copper azurins. Phys. Chem. Chem. Phys. 2018, 20, 30392– 30402,  DOI: 10.1039/C8CP06862C
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    Ab initio electronic structure calculations of entire blue copper azurins
    Romero-Muniz, Carlos; Ortega, Maria; Vilhena, J. G.; Diez-Perez, I.; Cuevas, Juan Carlos; Perez, Ruben; Zotti, Linda A.
    Physical Chemistry Chemical Physics (2018), 20 (48), 30392-30402CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
    We present a theor. study of the blue-copper azurin extd. from Pseudomonas aeruginosa and several of its single amino acid mutants. For the 1st time, we consider the whole structure of this kind of protein rather than limiting our anal. to the copper complex only. This was accomplished by combining fully ab initio calcns. based on DFT with at.-scale mol. dynamics simulations. Beyond the main features arising from the copper complex, our study revealed the role played by the peripheral parts of the proteins. In particular, we found that oxygen atoms belonging to carboxyl groups which are distributed all over the protein contributed to electronic states near the HOMO. The contribution of the outer regions to the electronic structure of azurins had so far been overlooked. The results highlight the need to investigate them thoroughly; this is esp. important in prospect of understanding complex processes such as electronic transport through metal-metalloprotein-metal junctions.
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    Zotti, L. A.; Bürkle, M.; Pauly, F.; Lee, W.; Kim, K.; Jeong, W.; Asai, Y.; Reddy, P.; Cuevas, J. C. Heat dissipation and its relation to thermopower in single-molecule junctions. New J. Phys. 2014, 16, 015004,  DOI: 10.1088/1367-2630/16/1/015004
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    Heat dissipation and its relation to thermopower in single-molecule junctions
    Zotti, L. A.; Burkle, M.; Pauly, F.; Lee, W.; Kim, K.; Jeong, W.; Asai, Y.; Reddy, P.; Cuevas, J. C.
    New Journal of Physics (2014), 16 (Jan.), 015004/1-015004/25, 25 pp.CODEN: NJOPFM; ISSN:1367-2630. (IOP Publishing Ltd.)
    Motivated by recent expts., we present here a detailed theor. anal. of the joule heating in current-carrying single-mol. junctions. By combining the Landauer approach for quantum transport with ab initio calcns., we show how the heating in the electrodes of a mol. junction is detd. by its electronic structure. In particular, we show that in general heat is not equally dissipated in both electrodes of the junction and it depends on the bias polarity (or equivalently on the current direction). These heating asymmetries are intimately related to the thermopower of the junction as both these quantities are governed by very similar principles. We illustrate these ideas by analyzing single-mol. junctions based on benzene derivs. with different anchoring groups. The close relation between heat dissipation and thermopower provides general strategies for exploring fundamental phenomena such as the Peltier effect or the impact of quantum interference effects on the joule heating of mol. transport junctions.
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    Cascella, M.; Magistrato, A.; Tavernelli, I.; Carloni, P.; Rothlisberger, U. Role of protein frame and solvent for the redox properties of azurin from Pseudomonas aeruginosa. Proc. Natl. Acad. Sci. U.S.A 2006, 103, 19641– 19646,  DOI: 10.1073/pnas.0607890103
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    Role of protein frame and solvent for the redox properties of azurin from Pseudomonas aeruginosa
    Cascella, Michele; Magistrato, Alessandra; Tavernelli, Ivano; Carloni, Paolo; Rothlisberger, Ursula
    Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (52), 19641-19646CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    We have coupled hybrid quantum mechanics (d. functional theory; Car-Parrinello)/mol. mechanics mol. dynamics simulations to a grand-canonical scheme, to calc. the in situ redox potential of the Cu2+ + - → Cu+ half reaction in azurin from Pseudomonas aeruginosa. An accurate description at atomistic level of the environment surrounding the metal-binding site and finite-temp. fluctuations of the protein structure are both essential for a correct quant. description of the electronic properties of this system. We report a redox potential shift with respect to copper in water of 0.2 eV (exptl. 0.16 eV) and a reorganization free energy λ = 0.76 eV (exptl. 0.6-0.8 eV). The electrostatic field of the protein plays a crucial role in fine tuning the redox potential and detg. the structure of the solvent. The inner-sphere contribution to the reorganization energy is negligible. The overall small value is mainly due to solvent rearrangement at the protein surface.
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    Corni, S. The reorganization energy of azurin in bulk solution and in the electrochemical scanning tunneling microscopy setup. J. Phys. Chem. B 2005, 109, 3423– 3430,  DOI: 10.1021/jp0459920
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    The Reorganization Energy of Azurin in Bulk Solution and in the Electrochemical Scanning Tunneling Microscopy Setup
    Corni, Stefano
    Journal of Physical Chemistry B (2005), 109 (8), 3423-3430CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
    The total reorganization energy λ of azurin is theor. studied both for the electron self-exchange reaction and for the protein in the electrochem. scanning tunneling microscopy (ECSTM) setup. The results demonstrate the importance of the proximity between the active sites in the encounter complex to reduce λ for the electron self-exchange reaction and quantifies the effects of the presence of an STM environment (tip and substrate) on λ. A comparison of the calcd. results with exptl. data is performed, and the relative magnitudes of the inner and outer contributions to λ are discussed.
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    Kontkanen, O. V.; Biriukov, D.; Futera, Z. Applicability of perturbed matrix method for charge transfer studies at bio/metallic interfaces: A case of azurin. Phys. Chem. Chem. Phys. 2023, 25, 12479– 12489,  DOI: 10.1039/D3CP00197K
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    Applicability of perturbed matrix method for charge transfer studies at bio/metallic interfaces: a case of azurin
    Kontkanen, Outi Vilhelmiina; Biriukov, Denys; Futera, Zdenek
    Physical Chemistry Chemical Physics (2023), 25 (17), 12479-12489CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
    As the field of nanoelectronics based on biomols. such as peptides and proteins rapidly grows, there is a need for robust computational methods able to reliably predict charge transfer properties at bio/metallic interfaces. Traditionally, hybrid quantum-mech./mol.-mech. techniques are employed for systems where the electron hopping transfer mechanism is applicable to det. phys. parameters controlling the thermodn. and kinetics of charge transfer processes. However, these approaches are limited by a relatively high computational cost when extensive sampling of a configurational space is required, like in the case of soft biomatter. For these applications, semi-empirical approaches such as the perturbed matrix method (PMM) have been developed and successfully used to study charge-transfer processes in biomols. Here, we explore the performance of PMM on prototypical redox-active protein azurin in various environments, from soln. to vacuum interfaces with gold surfaces and protein junction. We systematically benchmarked the robustness and convergence of the method with respect to the quantum-center size, size of the Hamiltonian, no. of samples, and level of theory. We show that PMM can adequately capture all the trends assocd. with the structural and electronic changes related to azurin oxidn. at bio/metallic interfaces.
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    Artés, J. M.; López-Martínez, M.; Giraudet, A.; Díez-Pérez, I.; Sanz, F.; Gorostiza, P. Current-voltage characteristics and transition voltage spectroscopy of individual redox proteins. J. Am. Chem. Soc. 2012, 134, 20218– 20221,  DOI: 10.1021/ja3080242
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    Current-Voltage Characteristics and Transition Voltage Spectroscopy of Individual Redox Proteins
    Artes, Juan M.; Lopez-Martinez, Montserrat; Giraudet, Arnaud; Diez-Perez, Ismael; Sanz, Fausto; Gorostiza, Pau
    Journal of the American Chemical Society (2012), 134 (50), 20218-20221CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Understanding how mol. conductance depends on voltage is essential for characterizing mol. electronics devices. We reproducibly measured current-voltage characteristics of individual redox-active proteins by scanning tunneling microscopy under potentiostatic control in both tunneling and wired configurations. From these results, transition voltage spectroscopy (TVS) data for individual redox mols. can be calcd. and analyzed statistically, adding a new dimension to conductance measurements. The transition voltage (TV) is discussed in terms of the two-step electron transfer (ET) mechanism. Azurin displays the lowest transition voltage measured to date (0.4 V), consistent with the previously reported distance decay factor. This low transition voltage may be advantageous for fabricating and operating mol. electronic devices for different applications. Our measurements show that transition voltage spectroscopy is a helpful tool for single-mol. ET measurements and suggest a mechanism for gating of electron transfer between partner redox proteins.

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  1. Gowtham Nirmal Jonnalagadda, Xiaojing Wu, Lukáš Hronek, Zdenek Futera. Structural, Solvent, and Temperature Effects on Protein Junction Conductance. The Journal of Physical Chemistry Letters 2024, 15 (46) , 11608-11614. https://doi.org/10.1021/acs.jpclett.4c02230
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  3. Kunchanapalli Ramya, Sabyasachi Mukhopadhyay. Investigation of numerical transport models in protein-based molecular junctions with cofactors of diverse chemical natures. Physica Scripta 2024, 99 (8) , 085968. https://doi.org/10.1088/1402-4896/ad61ce
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  • Abstract

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    Figure 1

    Figure 1. (a) Initial (i, iii) and final (ii, iv) geometries for the MD simulations mimicking junction formation through blinking (left) and side-indentation (right), respectively. (b) Schematic representation of the electron-transport mechanism taking place in a metal–azurin–metal junction via hopping through the Cu ion. (c) Schematic representation of the three cases considered for the level alignments.

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    Figure 2

    Figure 2. Hopping currents through one site in the blinking (a) and lateral (b) scheme for the HOMO-dominated, symmetric, and LUMO-dominated cases.

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    Figure 3

    Figure 3. (a) Temperature dependence of the one-site hopping currents obtained for blinking (at t = 466.6 ns) and for the lateral indentation (for d = 2.54 nm). (b) Barplot with the values of the fitting parameter B of eq 15 for all cases considered.

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    Figure 4

    Figure 4. One-site hopping and coherent-transport IV curves for three selected MD time frames of the blinking (a) and the lateral indentation (b) simulations in the HOMO-dominated, symmetric, and LUMO-dominated cases.

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    Figure 5

    Figure 5. Comparison between the current obtained for one-site and three-site hopping for different values of the reorganization energies of the two sets of residues forming the first and third sites (λL and λR, respectively). These specific data were extracted from the lateral-indentation scheme for d = 2.54 nm.

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  • References

    This article references 42 other publications.

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      Jiang, T.; Zeng, B.-F.; Zhang, B.; Tang, L. Single-molecular protein-based bioelectronics via electronic transport: fundamentals, devices and applications. Chem. Soc. Rev. 2023, 52, 5968– 6002,  DOI: 10.1039/D2CS00519K
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      Single-molecular protein-based bioelectronics via electronic transport: fundamentals, devices and applications
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      Chemical Society Reviews (2023), 52 (17), 5968-6002CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Biomol. electronics is a rapidly growing multidisciplinary field that combines biol., nanoscience, and engineering to bridge the two important fields of life sciences and mol. electronics. Proteins are remarkable for their ability to recognize mols. and transport electrons, making the integration of proteins into electronic devices a long sought-after goal and leading to the emergence of the field of protein-based bioelectronics, also known as proteotronics. This field seeks to design and create new biomol. electronic platforms that allow for the understanding and manipulation of protein-mediated electronic charge transport and related functional applications. In recent decades, there have been numerous reports on protein-based bioelectronics using a variety of nano-gapped elec. devices and techniques at the single mol. level, which are not achievable with conventional ensemble approaches. This review focuses on recent advances in phys. electron transport mechanisms, device fabrication methodologies, and various applications in protein-based bioelectronics. We discuss the most recent progress of the single or few protein-bridged elec. junction fabrication strategies, summarize the work on fundamental and functional applications of protein bioelectronics that enable high and dynamic electron transport, and highlight future perspectives and challenges that still need to be addressed. We believe that this specific review will stimulate the interdisciplinary research of topics related to protein-related bioelectronics, and open up new possibilities for single-mol. biophysics and biomedicine.
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      Ha, T. Q.; Planje, I. J.; White, J. R. G.; Aragonès, A. C.; Díez-Pérez, I. Charge transport at the protein–electrode interface in the emerging field of BioMolecular Electronics. Curr. Opin. Electrochem. 2021, 28, 100734,  DOI: 10.1016/j.coelec.2021.100734
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      Current Opinion in Electrochemistry (2021), 28 (), 100734CODEN: COEUCY; ISSN:2451-9111. (Elsevier B.V.)
      A review. The first is to use nature's efficient charge transport mechanisms as an inspiration to build the next generation of hybrid bioelectronic devices towards a more sustainable, biocompatible and efficient technol. The second is to understand this ubiquitous physicochem. process in life, exploited in many fundamental biol. processes such as cell signalling, respiration, photosynthesis or enzymic catalysis, leading us to a better understanding of disease mechanisms connected to charge diffusion. Extg. elec. signatures from a protein requires optimized methods for tethering the mols. to an electrode surface, where it is advantageous to have precise electrochem. control over the energy levels of the hybrid protein-electrode interface. Here, we review recent progress towards understanding the charge transport mechanisms through protein-electrode-protein junctions, which has led to the rapid development of the new BioMol. Electronics field. The field has brought a new vision into the mol. electronics realm, wherein complex supramol. structures such as proteins can efficiently transport charge over long distances when placed in a hybrid bioelectronic device. Such anomalous long-range charge transport mechanisms acutely depend on specific chem. modifications of the supramol. protein structure and on the precisely engineered protein-electrode chem. interactions. Key areas to explore in more detail are parameters such as protein stiffness (dynamics) and intrinsic electrostatic charge and how these influence the transport pathways and mechanisms in such hybrid devices.
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      Krishnan, S.; Aksimentiev, A.; Lindsay, S.; Matyushov, D. Long-Range Conductivity in Proteins Mediated by Aromatic Residues. ACS Phys. Chem. Au 2023, 3, 444,  DOI: 10.1021/acsphyschemau.3c00017
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      Long-Range Conductivity in Proteins Mediated by Aromatic Residues
      Krishnan, Siddharth; Aksimentiev, Aleksei; Lindsay, Stuart; Matyushov, Dmitry
      ACS Physical Chemistry Au (2023), 3 (5), 444-455CODEN: APCACH; ISSN:2694-2445. (American Chemical Society)
      Single-mols. measurements show that many proteins, lacking any redox cofactors, nonetheless exhibit elec. conductance on the order of a nanosiemen over 10 nm distances, implying that electrons can transit an entire protein in less than a nanosecond when subject to a p.d. of less than 1 V. This is puzzling because, for fast transport (i.e., a free energy barrier of zero), the hopping rate is detd. by the reorganization energy of approx. 0.8 eV, and this sets the time scale of a single hop to at least 1μs. Furthermore, the Fermi energies of typical metal electrodes are far removed from the energies required for sequential oxidn. and redn. of the arom. residues of the protein, which should further reduce the hopping current. Here, we combine all-atom mol. dynamics (MD) simulations of non-redox-active proteins (consensus tetratricopeptide repeats) with an electron transfer theory to demonstrate a mol. mechanism that can account for the unexpectedly fast electron transport. According to our MD simulations, the reorganization energy produced by the energy shift on charging (the Stokes shift) is close to the conventional value of 0.8 eV. However, the non-ergodic sampling of mol. configurations by the protein results in reaction-reorganization energies, extd. directly from the distribution of the electrostatic energy fluctuations, that are only ∼0.2 eV, which is small enough to enable long-range cond., without invoking quantum coherent transport. Using the MD values of the reorganization energies, we calc. a current decay with distance that is in agreement with expt.
    4. 4
      Bostick, C. D.; Mukhopadhyay, S.; Pecht, I.; Sheves, M.; Cahen, D.; Lederman, D. Protein Bioelectronics: A review of what we do and do not know. Rep. Prog. Phys. 2018, 81, 026601,  DOI: 10.1088/1361-6633/aa85f2
      4
      Protein bioelectronics: a review of what we do and do not know
      Bostick, Christopher D.; Mukhopadhyay, Sabyasachi; Pecht, Israel; Sheves, Mordechai; Cahen, David; Lederman, David
      Reports on Progress in Physics (2018), 81 (2), 026601/1-026601/57CODEN: RPPHAG; ISSN:1361-6633. (IOP Publishing Ltd.)
      A review. We review the status of protein-based mol. electronics. First, we define and discuss fundamental concepts of electron transfer and transport in and across proteins and proposed mechanisms for these processes. We then describe the immobilization of proteins to solid-state surfaces in both nanoscale and macroscopic approaches, and highlight how different methodologies can alter protein electronic properties. Because immobilizing proteins while retaining biol. activity is crucial to the successful development of bioelectronic devices, we discuss this process at length. We briefly discuss computational predictions and their connection to exptl. results. We then summarize how the biol. activity of immobilized proteins is beneficial for bioelectronic devices, and how conductance measurements can shed light on protein properties. Finally, we consider how the research to date could influence the development of future bioelectronic devices.
    5. 5
      Eleonora, A.; Reggiani, L.; Pousset, J. Proteotronics: Electronic devices based on proteins. Sensors 2015, 319, 3– 7,  DOI: 10.1007/978-3-319-09617-9_1
      There is no corresponding record for this reference.
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      Qiu, X.; Chiechi, R. C. Printable logic circuits comprising self-assembled protein complexes. Nat. Commun. 2022, 13, 2312,  DOI: 10.1038/s41467-022-30038-8
      6
      Printable logic circuits comprising self-assembled protein complexes
      Qiu, Xinkai; Chiechi, Ryan C.
      Nature Communications (2022), 13 (1), 2312CODEN: NCAOBW; ISSN:2041-1723. (Nature Portfolio)
      This paper describes the fabrication of digital logic circuits comprising resistors and diodes made from protein complexes and wired together using printed liq. metal electrodes. These resistors and diodes exhibit temp.-independent charge-transport over a distance of approximatley 10 nm and require no encapsulation or special handling. The function of the protein complexes is detd. entirely by self-assembly. When induced to self-assembly into anisotropic monolayers, the collective action of the aligned dipole moments increases the elec. cond. of the ensemble in one direction and decreases it in the other. When induced to self-assemble into isotropic monolayers, the dipole moments are randomized and the elec. cond. is approx. equal in both directions. We demonstrate the robustness and utility of these all-protein logic circuits by constructing pulse modulators based on AND and OR logic gates that function nearly identically to simulated circuits. These show that digital circuits with useful functionality can be derived from readily obtainable biomols. using simple, straightforward fabrication techniques that exploit mol. self-assembly, realizing one of the primary goals of mol. electronics.
    7. 7
      Artés, J. M.; Díez-Pérez, I.; Sanz, F.; Gorostiza, P. Direct measurement of electron transfer distance decay constants of single redox proteins by electrochemical tunneling spectroscopy. ACS Nano 2011, 5, 2060– 2066,  DOI: 10.1021/nn103236e
      7
      Direct Measurement of Electron Transfer Distance Decay Constants of Single Redox Proteins by Electrochemical Tunneling Spectroscopy
      Artes, Juan M.; Diez-Perez, Ismael; Sanz, Fausto; Gorostiza, Pau
      ACS Nano (2011), 5 (3), 2060-2066CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      We present a method to measure directly and at the single-mol. level the distance decay const. that characterizes the rate of electron transfer (ET) in redox proteins. Using an electrochem. tunneling microscope under bipotentiostatic control, we obtained current-distance spectroscopic recordings of individual redox proteins confined within a nanometric tunneling gap at a well-defined mol. orientation. The tunneling current decays exponentially, and the corresponding decay const. (β) strongly supports a two-step tunneling ET mechanism. Statistical anal. of decay const. measurements reveals differences between the reduced and oxidized states that may be relevant to the control of ET rates in enzymes and biol. electron transport chains.
    8. 8
      Ing, N. L.; El-Naggar, M. Y.; Hochbaum, A. I. Going the distance: Long-range conductivity in protein and peptide bioelectronic materials. J. Phys. Chem. B 2018, 122, 10403– 10423,  DOI: 10.1021/acs.jpcb.8b07431
      8
      Going the Distance: Long-Range Conductivity in Protein and Peptide Bioelectronic Materials
      Ing, Nicole L.; El-Naggar, Mohamed Y.; Hochbaum, Allon I.
      Journal of Physical Chemistry B (2018), 122 (46), 10403-10423CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      A review. Bioelectronic materials interface biomols., cells, organs, or organisms with electronic devices, and they represent an active and growing field of materials research. Protein and peptide nanostructures are ideal bioelectronic materials. They possess many of the properties required for biocompatibility across scales from enzymic to organismal interfaces, and recent examples of supramol. protein and peptide nanostructures exhibit impressive electronic properties. The ability of such natural and synthetic protein and peptide materials to conduct electricity over micrometer to centimeter length scales, however, is not readily understood from a conventional view of their amino acid building blocks. Distinct in structure and properties from solid-state inorg. and synthetic org. metals and semiconductors, supramol. conductive proteins and peptides require careful theor. treatment and exptl. characterization methods to understand their electronic structure. In this review, we discuss theory and exptl. evidence from recent literature describing the long-range conduction of electronic charge in protein and peptide materials. Electron transfer across proteins has been studied extensively, but application of models for such short-range charge transport to longer distances relevant to bioelectronic materials are less well-understood. Implementation of electronic band structure and electron transfer formulations in extended biomol. systems will be covered in the context of recent materials discoveries and efforts at characterization of electronic transport mechanisms.
    9. 9
      Romero-Muñiz, C.; Vilhena, J. G.; Pérez, R.; Cuevas, J. C.; Zotti, L. A. Recent advances in understanding the electron transport through metal-azurin-metal junctions. Front. Phys. 2022,  DOI: 10.3389/fphy.2022.950929
      There is no corresponding record for this reference.
    10. 10
      Sang, Y.; Mishra, S.; Tassinari, F.; Karuppannan, S. K.; Carmieli, R.; Teo, R. D.; Migliore, A.; Beratan, D. N.; Gray, H. B.; Pecht, I. Temperature dependence of charge and spin transfer in azurin. J. Phys. Chem. C 2021, 125, 9875– 9883,  DOI: 10.1021/acs.jpcc.1c01218
      10
      Temperature Dependence of Charge and Spin Transfer in Azurin
      Sang, Yutao; Mishra, Suryakant; Tassinari, Francesco; Kumar, Karuppannan S.; Carmieli, Raanan; Teo, Ruijie D.; Migliore, Agostino; Beratan, David N.; Gray, Harry B.; Pecht, Israel; Fransson, Jonas; Waldeck, David H.; Naaman, Ron
      Journal of Physical Chemistry C (2021), 125 (18), 9875-9883CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      The steady-state charge and spin transfer yields were measured for three different Ru-modified azurin derivs. in protein films on silver electrodes. While the charge-transfer yields exhibit weak temp. dependences, consistent with operation of a near activation-less mechanism, the spin selectivity of the electron transfer improves as temp. increases. This enhancement of spin selectivity with temp. is explained by a vibrationally induced spin exchange interaction between the Cu(II) and its chiral ligands. Distinct mechanisms control charge and spin transfer within proteins. As with electron charge transfer, proteins deliver polarized electron spins with a yield that depends on the protein's structure. This finding suggests a new role for protein structure in biochem. redox processes.
    11. 11
      Ortega, M.; Vilhena, J. G.; Zotti, L. A.; Díez-Pérez, I.; Cuevas, J. C.; Pérez, R. Tuning structure and dynamics of blue copper azurin junctions via single amino-acid mutations. Biomolecules 2019, 9, 611,  DOI: 10.3390/biom9100611
      11
      Tuning structure and dynamics of blue copper azurin junctions via single amino-acid mutations
      Ortega, Maria; Vilhena, J. G.; Zotti, Linda A.; Diez-Perez, Ismael; Cuevas, Juan Carlos; Perez, Ruben
      Biomolecules (2019), 9 (10), 611CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)
      Here we address this issue using all-atom Mol. Dynamics (MD) of Pseudomonas Aeruginosa Azurin adsorbed to a Au(111) substrate. In particular, we focus on the structure and dynamics of the free/adsorbed protein and how these properties are altered upon single-point mutations. The results revealed that wild-type Azurin adsorbs on Au(111) along two well defined configurations: one tethered via cysteine groups and the other via the hydrophobic pocket surrounding the Cu2+. Surprisingly, our simulations revealed that single amino-acid mutations gave rise to a quenching of protein vibrations ultimately resulting in its overall stiffening. Given the role of amino-acid vibrations and reorientation in the dehydration process at the protein-water-substrate interface, we suggest that this might have an effect on the adsorption process of the mutant, giving rise to new adsorption configurations.
    12. 12
      Kayser, B.; Fereiro, J. A.; Bhattacharyya, R.; Cohen, S. R.; Vilan, A.; Pecht, I.; Sheves, M.; Cahen, D. Solid-State Electron Transport via the Protein Azurin is Temperature-Independent Down to 4 K. J. Phys. Chem. Lett. 2020, 11, 144– 151,  DOI: 10.1021/acs.jpclett.9b03120
      12
      Solid-state electron transport via the protein azurin is temperature-independent down to 4 K
      Kayser, Ben; Fereiro, Jerry A.; Bhattacharyya, Rajarshi; Cohen, Sidney R.; Vilan, Ayelet; Pecht, Israel; Sheves, Mordechai; Cahen, David
      Journal of Physical Chemistry Letters (2020), 11 (1), 144-151CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)
      Solid-state electronic transport (ETp) via the electron-transfer copper protein azurin (Az) was measured in Au/Az/Au junction configurations down to 4 K, the lowest temp. for solid-state protein-based junctions. Not only does lowering the temp. help when observing fine features of electronic transport, but it also limits possible electron transport mechanisms. Practically, wire-bonded devices-on-chip, carrying Az-based microscopic junctions, were measured in liq. He, minimizing temp. gradients across the samples. Much smaller junctions, in conducting-probe at. force microscopy measurements, served, between room temp. and the protein's denaturation temp. (∼323 K), to check that conductance behavior is independent of device configuration or contact nature and thus is a property of the protein itself. Temp.-independent currents were obsd. from ∼320 to 4 K. The exptl. results were fitted to a single-level Landauer model to ext. effective energy barrier and electrode-mol. coupling strength values and to compare data sets. Our results strongly support that quantum tunneling, rather than hopping, dominates ETp via Az.
    13. 13
      Artés, J. M.; López-Martínez, M.; Díez-Pérez, I.; Sanz, F.; Gorostiza, P. Conductance switching in single wired redox proteins. Small 2014, 10, 2537– 2541,  DOI: 10.1002/smll.201303753
      13
      Conductance Switching in Single Wired Redox Proteins
      Artes, Juan M.; Lopez-Martinez, Montserrat; Diez-Perez, Ismael; Sanz, Fausto; Gorostiza, Pau
      Small (2014), 10 (13), 2537-2541CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)
      We report the observation of switching evens in spontaneously formed single wire protein junctions in an electrochem. environment.
    14. 14
      Ruiz, M. P.; Aragonès, A. C.; Camarero, N.; Vilhena, J. G.; Ortega, M.; Zotti, L. A.; Pérez, R.; Cuevas, J. C.; Gorostiza, P.; Díez-Pérez, I. Bioengineering a single-protein junction. J. Am. Chem. Soc. 2017, 139, 15337– 15346,  DOI: 10.1021/jacs.7b06130
      14
      Bioengineering a Single-Protein Junction
      Ruiz, Marta P.; Aragones, Albert C.; Camarero, Nuria; Vilhena, J. G.; Ortega, Maria; Zotti, Linda A.; Perez, Ruben; Cuevas, Juan Carlos; Gorostiza, Pau; Diez-Perez, Ismael
      Journal of the American Chemical Society (2017), 139 (43), 15337-15346CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Bioelectronics moves toward designing nanoscale electronic platforms that allow in vivo detns. Such devices require interfacing complex biomol. moieties as the sensing units to an electronic platform for signal transduction. Inevitably, a systematic design goes through a bottom-up understanding of the structurally related elec. signatures of the biomol. circuit, which will ultimately lead researchers to tailor its elec. properties. Toward this aim, the authors show here the first example of bioengineered charge transport in a single-protein elec. contact. A single point-site mutation at the docking hydrophobic patch of a Cu-azurin causes minor structural distortion of the protein blue Cu site and a dramatic change in the charge transport regime of the single-protein contact, which goes from the classical Cu-mediated two-step transport in this system to a direct coherent tunneling. The authors' extensive spectroscopic studies and mol.-dynamics simulations show that the proteins' folding structures are preserved in the single-protein junction. The DFT-computed frontier orbital of the relevant protein segments suggests that the Cu center participation in each protein variant accounts for the different obsd. charge transport behavior. This work is a direct evidence of charge transport control in a protein backbone through external mutagenesis and a unique nanoscale platform to study structurally related biol. electron transfer.
    15. 15
      Valianti, S.; Cuevas, J. C.; Skourtis, S. S. Charge-transport mechanisms in azurin-based monolayer junctions. J. Phys. Chem. C 2019, 123, 5907– 5922,  DOI: 10.1021/acs.jpcc.9b00135
      15
      Charge-Transport Mechanisms in Azurin-Based Monolayer Junctions
      Valianti, Stephanie; Cuevas, Juan-Carlos; Skourtis, Spiros S.
      Journal of Physical Chemistry C (2019), 123 (10), 5907-5922CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      We study the transport mechanisms of different types of azurin (Az) monolayer heterojunctions with a variety of metal substituents. The systems include Holo-Az (Cu-substituted), Apo-Az (no metal), and Ni-, Co- and Zn-substituted azurins. Our theor. anal. is based on measurements of the voltage and temp. dependencies of the current and attempts to reproduce both dependencies using a common mechanism and corresponding set of parameters. Our results strongly suggest that for Holo-Az the transport mechanism depends on the protein monolayer/heterojunction setup. In one type of heterojunction, transport is dominated by resonant incoherent hopping through the Cu redox site, whereas in the other it is mediated by off-resonant tunneling. For the unsubstituted (Apo-Az) and other metal-substituted azurins, the dominant transport mechanism at low temps. is off-resonant tunneling, with an av. tunneling barrier that depends on the type of metal dopant, and at the highest temps., it is through-amino-acid hopping. Our modeling results are relevant to the anal. of the current behavior over a range of temps. for any mol. heterojunction device.
    16. 16
      Amdursky, N.; Marchak, D.; Sepunaru, L.; Pecht, I.; Sheves, M.; Cahen, D. Electronic transport via proteins. Adv. Mater. 2014, 26, 7142– 7161,  DOI: 10.1002/adma.201402304
      16
      Electronic Transport via Proteins
      Amdursky, Nadav; Marchak, Debora; Sepunaru, Lior; Pecht, Israel; Sheves, Mordechai; Cahen, David
      Advanced Materials (Weinheim, Germany) (2014), 26 (42), 7142-7161CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. A central vision in mol. electronics is the creation of devices with functional mol. components that may provide unique properties. Proteins are attractive candidates for this purpose, as they have specific phys. (optical, elec.) and chem. (selective binding, self-assembly) functions and offer a myriad of possibilities for (bio-)chem. modification. This Progress Report focuses on proteins as potential building components for future bioelectronic devices as they are quite efficient electronic conductors, compared with satd. org. mols. The report addresses several questions: how general is this behavior; how does protein conduction compare with that of satd. and conjugated mols.; and what mechanisms enable efficient conduction across these large mols. To answer these questions results of nanometer-scale and macroscopic electronic transport measurements across a range of org. mols. and proteins are compiled and analyzed, from single/few mols. to large mol. ensembles, and the influence of measurement methods on the results is considered. Generalizing, it is found that proteins conduct better than satd. mols., and somewhat poorer than conjugated mols. Significantly, the presence of cofactors (redox-active or conjugated) in the protein enhances their conduction, but without an obvious advantage for natural electron transfer proteins. Most likely, the conduction mechanisms are hopping (at higher temps.) and tunneling (below ca. 150-200 K).
    17. 17
      Artés, J. M.; Díez-Pérez, I.; Gorostiza, P. Transistor-like behavior of single metalloprotein junctions. Nano Lett. 2012, 12, 2679– 2684,  DOI: 10.1021/nl2028969
      17
      Transistor-like Behavior of Single Metalloprotein Junctions
      Artes, Juan M.; Diez-Perez, Ismael; Gorostiza, Pau
      Nano Letters (2012), 12 (6), 2679-2684CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
      Single protein junctions consisting of azurin bridged between a gold substrate and the probe of an electrochem. tunneling microscope (ECSTM) were obtained by two independent methods that allowed statistical anal. over a large no. of measured junctions. Conductance measurements yield (7.3 ± 1.5) × 10-6G0 in agreement with reported ests. using other techniques. Redox gating of the protein with an on/off ratio of 20 was demonstrated and constitutes a proof-of-principle of a single redox protein field-effect transistor.
    18. 18
      Romero-Muñiz, C.; Ortega, M.; Vilhena, J. G.; Díez-Pérez, I.; Pérez, R.; Cuevas, J. C.; Zotti, L. A. Can. electron transport through a blue-copper azurin be coherent? An ab initio study. J. Phys. Chem. C 2021, 125, 1693– 1702,  DOI: 10.1021/acs.jpcc.0c09364
      18
      Can Electron Transport through a Blue-Copper Azurin Be Coherent? An Ab Initio Study
      Romero-Muniz, Carlos; Ortega, Maria; Vilhena, J. G.; Diez-Perez, Ismael; Perez, Ruben; Cuevas, Juan Carlos; Zotti, Linda A.
      Journal of Physical Chemistry C (2021), 125 (3), 1693-1702CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      Multiple expts. on the electron transport through solid-state junctions based on different proteins suggested that the dominant transport mechanism is quantum tunneling (or coherent transport). This is extremely surprising given the length of these mols. (2-7 nm) and their electronic structure (mainly comprising very localized MOs). Overall, this is probably the single most important puzzle in the field of biomol. electronics and calls for rigorous calcns. of the tunneling probability in protein-based junctions. Motivated by these expts., the authors tackle here this problem and report a comprehensive theor. study of the coherent electron transport in metal-protein-metal junctions based on the blue-copper azurin from Pseudomonas aeruginosa, which is the workhorse in protein electronics. More precisely, the authors focus on single-mol. junctions realized in STM-based expts. and analyze a wide variety of contact scenarios. The authors' calcns. are based on a combination of mol. dynamics simulations and ab initio transport calcns. The authors' results unambiguously show that when azurin is not deformed and retains its pristine structure, the end-to-end tunneling probability is exceedingly small and does not give rise to any measurable elec. current. However, much higher tunneling probabilities are possible when either the STM tip (indented from the top) substantially compresses the protein or the protein is contacted sideways, significantly reducing the effective junction length. Also in certain configurations, the presence of surrounding water can also increase the conductance but it cannot explain the high conductance values reported exptl. In all cases, the current is found to flow through the Cu atom of this metalloprotein, although the role of several other levels close to the Fermi energy cannot be ruled out. The authors remark that the authors only evaluate the efficiency of coherent transport and the anal. of the relevance of other potential charge-transport mechanisms is out of the scope of the authors' work.
    19. 19
      Yu, X.; Lovrincic, R.; Sepunaru, L.; Li, W.; Vilan, A.; Pecht, I.; Sheves, M.; Cahen, D. Insights into solid-state electron transport through proteins from inelastic tunneling spectroscopy: The case of azurin. ACS Nano 2015, 9, 9955– 9963,  DOI: 10.1021/acsnano.5b03950
      19
      Insights into Solid-State Electron Transport through Proteins from Inelastic Tunneling Spectroscopy: The Case of Azurin
      Yu, Xi; Lovrincic, Robert; Sepunaru, Lior; Li, Wenjie; Vilan, Ayelet; Pecht, Israel; Sheves, Mordechai; Cahen, David
      ACS Nano (2015), 9 (10), 9955-9963CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Surprisingly efficient solid-state electron transport has recently been demonstrated through "dry" proteins (with only structural, tightly bound H2O left), suggesting proteins as promising candidates for mol. (bio)electronics. Using inelastic electron tunneling spectroscopy (IETS), we explored electron-phonon interaction in metal/protein/metal junctions, to help understand solid-state electronic transport across the redox protein azurin. To that end an oriented azurin monolayer on Au is contacted by soft Au electrodes. Characteristic vibrational modes of amide and amino acid side groups as well as of the azurin-electrode contact were obsd., revealing the azurin native conformation in the junction and the crit. role of side groups in the charge transport. The lack of abrupt changes in the conductance and the line shape of IETS point to far off-resonance tunneling as the dominant transport mechanism across azurin, in line with previously reported (and herein confirmed) azurin junctions. The inelastic current and hence electron-phonon interaction appear to be rather weak and comparable in magnitude with the inelastic fraction of tunneling current via alkyl chains, which may reflect the known structural rigidity of azurin.
    20. 20
      Papp, E.; Vattay, G.; Romero-Muñiz, C.; Zotti, L. A.; Fereiro, J. A.; Sheves, M.; Cahen, D. Experimental data confirm carrier-cascade model for solid-state conductance across proteins. J. Phys. Chem. B 2023, 127, 1728– 1734,  DOI: 10.1021/acs.jpcb.2c07946
      20
      Experimental Data Confirm Carrier-Cascade Model for Solid-State Conductance across Proteins
      Papp, Eszter; Vattay, Gabor; Romero-Muniz, Carlos; Zotti, Linda A.; Fereiro, Jerry A.; Sheves, Mordechai; Cahen, David
      Journal of Physical Chemistry B (2023), 127 (8), 1728-1734CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      The finding that electronic conductance across ultrathin protein films between metallic electrodes remains nearly const. from room temp. to just a few K has posed a challenge. We show that a model based on a generalized Landauer formula explains the nearly const. conductance and predicts an Arrhenius-like dependence for low temps. A crit. aspect of the model is that the relevant activation energy for conductance is either the difference between the HOMO and HOMO-1 or the LUMO+1 and LUMO energies instead of the HOMO-LUMO gap of the proteins. Anal. of exptl. data confirms the Arrhenius-like law and allows us to ext. the activation energies. We then calc. the energy differences with advanced DFT methods for proteins used in the expts. Our main result is that the exptl. and theor. activation energies for these three different proteins and three differently prepd. solid-state junctions match nearly perfectly, implying the mechanism's validity.
    21. 21
      Romero-Muñiz, C.; Ortega, M.; Vilhena, J. G.; Pérez, R.; Cuevas, J. C.; Zotti, L. A. The role of metal ions in the electron transport through azurin-based junctions. Appl. Sci. 2021, 11, 3732,  DOI: 10.3390/app11093732
      21
      The role of metal ions in the electron transport through azurin-based junctions
      Romero-Muniz, Carlos; Ortega, Maria; Vilhena, Jose Guilherme; Perez, Ruben; Cuevas, Juan Carlos; Zotti, Linda A.
      Applied Sciences (2021), 11 (9), 3732CODEN: ASPCC7; ISSN:2076-3417. (MDPI AG)
      We studied the coherent electron transport through metal-protein-metal junctions based on a blue copper azurin, in which the copper ion was replaced by three different metal ions (Co, Ni and Zn). Our results show that neither the protein structure nor the transmission at the Fermi level change significantly upon metal replacement. The discrepancy with previous exptl. observations suggests that the transport mechanism taking place in these types of junctions is probably not fully coherent.
    22. 22
      Romero-Muñiz, C.; Ortega, M.; Vilhena, J. G.; Diéz-Pérez, I.; Cuevas, J. C.; Pérez, R.; Zotti, L. A. Mechanical deformation and electronic structure of a blue copper azurin in a solid-state junction. Biomolecules 2019, 9, 506,  DOI: 10.3390/biom9090506
      22
      Mechanical deformation and electronic structure of a blue copper azurin in a solid-state junction
      Romero-Muniz, Carlos; Ortega, Maria; Vilhena, J. G.; Diez-Perez, Ismael; Cuevas, Juan Carlos; Perez, Ruben; Zotti, Linda A.
      Biomolecules (2019), 9 (9), 506CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)
      Protein-based electronics is an emerging field which has attracted considerable attention over the past decade. Here, we present a theor. study of the formation and electronic structure of a metal-protein-metal junction based on the blue-copper azurin from pseudomonas aeruginosa. We focus on the case in which the protein is adsorbed on a gold surface and is contacted, at the opposite side, to an STM (Scanning Tunneling Microscopy) tip by spontaneous attachment. This has been simulated through a combination of mol. dynamics and d. functional theory. We find that the attachment to the tip induces structural changes in the protein which, however, do not affect the overall electronic properties of the protein. Indeed, only changes in certain residues are obsd., whereas the electronic structure of the Cu-centered complex remains unaltered, as does the total d. of states of the whole protein.
    23. 23
      Ozaki, T. Variationally optimized atomic orbitals for large-scale electronic structures. Phys. Rev. B 2003, 67, 155108,  DOI: 10.1103/PhysRevB.67.155108
      23
      Variationally optimized atomic orbitals for large-scale electronic structures
      Ozaki, T.
      Physical Review B: Condensed Matter and Materials Physics (2003), 67 (15), 155108/1-155108/5CODEN: PRBMDO; ISSN:0163-1829. (American Physical Society)
      A simple and practical method for variationally optimizing numerical AOs used in d. functional calcns. is presented based on the force theorem. The derived equation provides the same procedure for the optimization of AOs as that for the geometry optimization. The optimized orbitals well reproduce convergent results calcd. by a larger no. of unoptimized orbitals. In addn., we demonstrate that the optimized orbitals significantly reduce the computational effort in the geometry optimization, while keeping a high degree of accuracy.
    24. 24
      Ozaki, T.; Kino, H. Numerical atomic basis orbitals from H to Kr. Phys. Rev. B 2004, 69, 195113,  DOI: 10.1103/PhysRevB.69.195113
      24
      Numerical atomic basis orbitals from H to Kr
      Ozaki, T.; Kino, H.
      Physical Review B: Condensed Matter and Materials Physics (2004), 69 (19), 195113/1-195113/19CODEN: PRBMDO; ISSN:0163-1829. (American Physical Society)
      We present a systematic study for numerical at. basis orbitals ranging from H to Kr, which could be used in large scale O(N) electronic structure calcns. based on d.-functional theories (DFT). The comprehensive investigation of convergence properties with respect to our primitive basis orbitals provides a practical guideline in an optimum choice of basis sets for each element, which well balances the computational efficiency and accuracy. Moreover, starting from the primitive basis orbitals, a simple and practical method for variationally optimizing basis orbitals is presented based on the force theorem, which enables us to maximize both the computational efficiency and accuracy. The optimized orbitals well reproduce convergent results calcd. by a larger no. of primitive orbitals. As illustrations of the orbital optimization, we demonstrate two examples: the geometry optimization coupled with the orbital optimization of a C60 mol. and the preorbital optimization for a specific group such as proteins. They clearly show that the optimized orbitals significantly reduce the computational efforts, while keeping a high degree of accuracy, thus indicating that the optimized orbitals are quite suitable for large scale DFT calcns.
    25. 25
      Amdursky, N.; Sepunaru, L.; Raichlin, S.; Pecht, I.; Sheves, M.; Cahen, D. Electron transfer proteins as electronic conductors: Significance of the metal and its binding site in the blue Cu protein, azurin. Adv. Sci. 2015, 2, 1400026,  DOI: 10.1002/advs.201400026
      25
      Electron Transfer Proteins as Electronic Conductors: Significance of the Metal and Its Binding Site in the Blue Cu Protein, Azurin
      Amdursky Nadav; Raichlin Sara; Sepunaru Lior; Cahen David; Pecht Israel; Sheves Mordechai
      Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2015), 2 (4), 1400026 ISSN:2198-3844.
      Electron transfer (ET) proteins are biomolecules with specific functions, selected by evolution. As such they are attractive candidates for use in potential bioelectronic devices. The blue copper protein azurin (Az) is one of the most-studied ET proteins. Traditional spectroscopic, electrochemical, and kinetic methods employed for studying ET to/from the protein's Cu ion have been complemented more recently by studies of electrical conduction through a monolayer of Az in the solid-state, sandwiched between electrodes. As the latter type of measurement does not require involvement of a redox process, it also allows monitoring electronic transport (ETp) via redox-inactive Az-derivatives. Here, results of macroscopic ETp via redox-active and -inactive Az derivatives, i.e., Cu(II) and Cu(I)-Az, apo-Az, Co(II)-Az, Ni(II)-Az, and Zn(II)-Az are reported and compared. It is found that earlier reported temperature independence of ETp via Cu(II)-Az (from 20 K until denaturation) is unique, as ETp via all other derivatives is thermally activated at temperatures >≈200 K. Conduction via Cu(I)-Az shows unexpected temperature dependence >≈200 K, with currents decreasing at positive and increasing at negative bias. Taking all the data together we find a clear compensation effect of Az conduction around the Az denaturation temperature. This compensation can be understood by viewing the Az binding site as an electron trap, unless occupied by Cu(II), as in the native protein, with conduction of the native protein setting the upper transport efficiency limit.
    26. 26
      Cuevas, J. C.; Scheer, E. Molecular electronics: An introduction to theory and experiment; World Scientific: 2017.
      There is no corresponding record for this reference.
    27. 27
      Valianti, S.; Skourtis, S. S. Observing donor-to-acceptor electron-transfer rates and the Marcus inverted parabola in Molecular Junctions. J. Phys. Chem. B 2019, 123, 9641– 9653,  DOI: 10.1021/acs.jpcb.9b07371
      27
      Observing Donor-to-Acceptor Electron-Transfer Rates and the Marcus Inverted Parabola in Molecular Junctions
      Valianti, Stephanie; Skourtis, Spiros S.
      Journal of Physical Chemistry B (2019), 123 (45), 9641-9653CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      A recurring theme in mol. electronics is the relationship between the intramol. electron transfer rate in a donor-bridge-acceptor system and the conductance at low bias in the corresponding electrode-bridge-electrode junction. The similarities between through-bridge donor-to-acceptor electron tunneling and through-bridge electrode-to-electrode Landauer transport led to the suggestion of an approx. linear relationship between the rate and the conductance for any given bridge. A large body of work indicates that the two quantities are not necessarily linearly related, showing different behaviors as a function of temp., voltage and bridge length. Apart from Landauer tunneling, incoherent hopping can be an important mechanism in mol. junctions. We propose a donor-bridge-acceptor mol. junction, functioning in the incoherent hopping regime, that is suited for establishing direct correlations between the electrode-to-electrode current and the intramol. donor-to-acceptor electron transfer rate. We suggest that this type of junction may be used to observe the Marcus-inverted-parabola dependence of the intramol. rate on energy gap by varying the bias voltage. The realization of such an expt. would enable meaningful comparisons between soln.-phase electron transfer rates and mol.-junction currents for the same mol.
    28. 28
      Migliore, A.; Nitzan, A. Nonlinear charge transport in redox molecular junctions: A Marcus perspective. ACS Nano 2011, 5, 6669– 6685,  DOI: 10.1021/nn202206e
      28
      Nonlinear Charge Transport in Redox Molecular Junctions: A Marcus Perspective
      Migliore, Agostino; Nitzan, Abraham
      ACS Nano (2011), 5 (8), 6669-6685CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Redox mol. junctions are mol. conduction junctions that involve more than one oxidn. state of the mol. bridge. This property is derived from the ability of the mol. to transiently localize transmitting electrons, implying relatively weak mol.-leads coupling and, in many cases, the validity of the Marcus theory of electron transfer. Here the authors study the implications of this property on the nonlinear transport properties of such junctions. The authors obtain an anal. soln. of the integral equations that describe mol. conduction in the Marcus kinetic regime and use it in different phys. limits to predict some important features of nonlinear transport in metal-mol.-metal junctions. In particular, conduction, rectification, and neg. differential resistance can be obtained in different regimes of interplay between two different conduction channels assocd. with different localization properties of the excess mol. charge, without specific assumptions about the electronic structure of the mol. bridge. The predicted behaviors show temp. dependences typically obsd. in the expt. The validity of the proposed model and ways to test its predictions and implement the implied control strategies are discussed.
    29. 29
      Markussen, T.; Jin, C.; Thygesen, K. S. Quantitatively accurate calculations of conductance and thermopower of molecular junctions. Phys. Status Solidi (b) 2013, 250, 2394– 2402,  DOI: 10.1002/pssb.201349217
      29
      Quantitatively accurate calculations of conductance and thermopower of molecular junctions
      Markussen, Troels; Jin, Chengjun; Thygesen, Kristian S.
      Physica Status Solidi B: Basic Solid State Physics (2013), 250 (11), 2394-2402CODEN: PSSBBD; ISSN:0370-1972. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Thermopower measurements of mol. junctions have recently gained interest as a characterization technique that supplements the more traditional conductance measurements. Here we investigate the electronic conductance and thermopower of benzenediamine (BDA) and benzenedicarbonitrile (BDCN) connected to gold electrodes using first-principles calcns. We find excellent agreement with expts. for both mols. when exchange-correlation effects are described by the many-body GW approxn. In contrast, results from std. d. functional theory (DFT) deviate from expts. by up to two orders of magnitude. The failure of DFT is particularly pronounced for the n-type BDCN junction due to the severe underestimation of the LUMO (LUMO). The quality of the DFT results can be improved by correcting the mol. energy levels for self-interaction errors and image charge effects. Finally, we show that the conductance and thermopower of the considered junctions are relatively insensitive to the metal-mol. bonding geometry. Our results demonstrate that electronic and thermoelec. properties of mol. junctions can be predicted from first-principles calcns. when exchange-correlation effects are taken properly into account.
    30. 30
      Haiss, W.; Nichols, R. J.; van Zalinge, H.; Higgins, S. J.; Bethell, D.; Schiffrin, D. J. Measurement of single molecule conductivity using the spontaneous formation of molecular wires. Phys. Chem. Chem. Phys. 2004, 6, 4330– 4337,  DOI: 10.1039/b404929b
      30
      Measurement of single molecule conductivity using the spontaneous formation of molecular wires
      Haiss, Wolfgang; Nichols, Richard J.; van Zalinge, Harm; Higgins, Simon J.; Bethell, Donald; Schiffrin, David J.
      Physical Chemistry Chemical Physics (2004), 6 (17), 4330-4337CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
      A technique to measure the elec. cond. of single mols. was demonstrated. The method is based on trapping mols. between an STM tip and a substrate. The spontaneous attachment and detachment of α,ω-alkanedithiol mol. wires was easily monitored in the time domain. Elec. contact between the target mol. and the gold probes was achieved using thiol groups present at each end of the mol. Characteristic jumps in the tunnelling current were obsd. when the tip was positioned at a const. height and the STM feedback loop was disabled. Histograms of the measured current jump values were used to calc. the mol. cond. as a function of bias and chain length. These measurements can be carried out in a variety of environments, including aq. electrolytes. The changes in cond. with chain length obtained are in agreement with previous results obtained using a conducting AFM and the origin of some discrepancies in the literature is analyzed.
    31. 31
      Haiss, W.; Wang, C.; Grace, I.; Batsanov, A. S.; Schiffrin, D. J.; Higgins, S. J.; Bryce, M. R.; Lambert, C. J.; Nichols, R. J. Precision control of single-molecule electrical junctions. Nat. Mater. 2006, 5, 995– 1002,  DOI: 10.1038/nmat1781
      31
      Precision control of single-molecule electrical junctions
      Haiss, Wolfgang; Wang, Changsheng; Grace, Iain; Batsanov, Andrei S.; Schiffrin, David J.; Higgins, Simon J.; Bryce, Martin R.; Lambert, Colin J.; Nichols, Richard J.
      Nature Materials (2006), 5 (12), 995-1002CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
      There is much discussion of mols. as components for future electronic devices. However, the contacts, the local environment and the temp. can all affect their elec. properties. This sensitivity, particularly at the single-mol. level, may limit the use of mols. as active elec. components, and therefore it is important to design and evaluate mol. junctions with a robust and stable elec. response over a wide range of junction configurations and temps. Here we report an approach to monitor the elec. properties of single-mol. junctions, which involves precise control of the contact spacing and tilt angle of the mol. Comparison with ab initio transport calcns. shows that the tilt-angle dependence of the elec. conductance is a sensitive spectroscopic probe, providing information about the position of the Fermi energy. It is also shown that the elec. properties of flexible mols. are dependent on temp., whereas those of mols. designed for their rigidity are not.
    32. 32
      Díez-Pérez, I.; Hihath, J.; Lee, Y.; Yu, L.; Adamska, L.; Kozhushner, M. A.; Oleynik, I. I.; Tao, N. Rectification and stability of a single molecular diode with controlled orientation. Nat. Chem. 2009, 1, 635,  DOI: 10.1038/nchem.392
      32
      Rectification and stability of a single molecular diode with controlled orientation
      Diez-Perez, Ismael; Hihath, Joshua; Lee, Youngu; Yu, Luping; Adamska, Lyudmyla; Kozhushner, Mortko A.; Oleynik, Ivan I.; Tao, Nongjian
      Nature Chemistry (2009), 1 (8), 635-641CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      In the mol. electronics field it is highly desirable to engineer the structure of mols. to achieve specific functions. In particular, diode (or rectification) behavior in single mols. is an attractive device function. Here the authors study charge transport through sym. tetra-Ph and nonsym. diblock dipyrimidinyldiphenyl mols. covalently bound to two electrodes. The orientation of the diblock is controlled through a selective deprotection strategy, and a method in which the electrode-electrode distance is modulated unambiguously dets. the current-voltage characteristics of the single-mol. device. The diblock mol. exhibits pronounced rectification behavior compared with its homologous sym. block, with current flowing from the dipyrimidinyl to the di-Ph moieties. This behavior is interpreted in terms of localization of the wave function of the hole ground state at one end of the diblock under the applied field. At large forward current, the mol. diode becomes unstable and quantum point contacts between the electrodes form.
    33. 33
      Aragonès, A. C.; Darwish, N.; Ciampi, S.; Sanz, F.; Gooding, J. J.; Díez-Pérez, I. Single-molecule electrical contacts on silicon electrodes under ambient conditions. Nat. Commun. 2017, 8, 15056,  DOI: 10.1038/ncomms15056
      33
      Single-molecule electrical contacts on silicon electrodes under ambient conditions
      Aragones, Albert C.; Darwish, Nadim; Ciampi, Simone; Sanz, Fausto; Gooding, J. Justin; Diez-Perez, Ismael
      Nature Communications (2017), 8 (), 15056CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
      The ultimate goal in mol. electronics is to use individual mols. as the active electronic component of a real-world sturdy device. For this concept to become reality, it will require the field of single-mol. electronics to shift towards the semiconducting platform of the current microelectronics industry. Here, we report silicon-based single-mol. contacts that are mech. and elec. stable under ambient conditions. The single-mol. contacts are prepd. on silicon electrodes using the scanning tunnelling microscopy break-junction approach using a top metallic probe. The mol. wires show remarkable current-voltage reproducibility, as compared to an open silicon/nano-gap/metal junction, with current rectification ratios exceeding 4,000 when a low-doped silicon is used. The extension of the single-mol. junction approach to a silicon substrate contributes to the next level of miniaturization of electronic components and it is anticipated it will pave the way to a new class of robust single-mol. circuits.
    34. 34
      Baldacchini, C.; Kumar, V.; Bizzarri, A. R.; Cannistraro, S. Electron tunnelling through single azurin molecules can be on/off switched by voltage pulses. Appl. Phys. Lett. 2015, 106, 183701,  DOI: 10.1063/1.4919911
      34
      Electron tunnelling through single azurin molecules can be on/off switched by voltage pulses
      Baldacchini, Chiara; Kumar, Vivek; Bizzarri, Anna Rita; Cannistraro, Salvatore
      Applied Physics Letters (2015), 106 (18), 183701/1-183701/4CODEN: APPLAB; ISSN:0003-6951. (American Institute of Physics)
      Redox metalloproteins are emerging as promising candidates for future bio-optoelectronic and nano-biomemory devices, and the control of their electron transfer properties through external signals is still a crucial task. Here, a reversible on/off switching of the electron current tunneling through a single protein can be achieved in azurin protein mols. adsorbed on gold surfaces, by applying appropriate voltage pulses through a scanning tunneling microscope tip. The obsd. changes in the hybrid system tunneling properties are discussed in terms of long-sustained charging of the protein milieu. (c) 2015 American Institute of Physics.
    35. 35
      Fereiro, J. A.; Bendikov, T.; Pecht, I.; Sheves, M.; Cahen, D. Protein binding and orientation matter: Bias-induced conductance switching in a mutated azurin junction. J. Am. Chem. Soc. 2020, 142, 19217– 19225,  DOI: 10.1021/jacs.0c08836
      35
      Protein Binding and Orientation Matter: Bias-Induced Conductance Switching in a Mutated Azurin Junction
      Fereiro, Jerry A.; Bendikov, Tatyana; Pecht, Israel; Sheves, Mordechai; Cahen, David
      Journal of the American Chemical Society (2020), 142 (45), 19217-19225CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Reversible, bias-induced switching of conductance via a blue copper protein azurin mutant, N42C Az, with a nearly 10-fold increase at |V| > 0.8 v than at lower bias. were obsd. No such switching is found for wild-type azurin, WT Az, up to |1.2 V|, beyond which irreversible changes occur. The N42C Az mutant will, when positioned between electrodes in a solid-state Au-protein-Au junction, have an orientation opposite that of WT Az with respect to the electrodes. Current(s) via both proteins are temp.-independent, consistent with quantum mech. tunneling as dominant transport mechanism. No noticeable difference is resolved between the two proteins in conductance and inelastic electron tunneling spectra at <|0.5 V| bias voltages. Switching behavior persists from 15 K up to room temp. The conductance peak is consistent with the system switching in and out of resonance with the changing bias. With further input from UV photoemission measurements on Au-protein systems, these striking differences in conductance are rationalized by having the location of the Cu(II) coordination sphere in the N42C Az mutant, proximal to the (larger) substrate-electrode, to which the protein is chem. bound, while for the WT Az that coordination sphere is closest to the other Au electrode, with which only phys. contact is made. The authors' results establish the key roles that a protein's orientation and binding nature to the electrodes play in detg. the electron transport tunnel barrier.
    36. 36
      Alessandrini, A.; Facci, P. Electron transfer in nanobiodevices. Eur. Polym. J. 2016, 83, 450– 466,  DOI: 10.1016/j.eurpolymj.2016.03.028
      36
      Electron transfer in nanobiodevices
      Alessandrini, Andrea; Facci, Paolo
      European Polymer Journal (2016), 83 (), 450-466CODEN: EUPJAG; ISSN:0014-3057. (Elsevier Ltd.)
      A review. The present tutorial is aimed at introducing the reader to the main aspects of electron transfer in nanobiodevices. Nanobiodevices are faced both from scientific and technol. viewpoints and their particular implementation as electron transfer devices provides the opportunity of presenting fundamentals of electron transfer theory. Examples of implementations of stand alone devices, along with those involving reconfigurable set-ups based on an electrochem. scanning tunneling microscope, enable introducing heterogeneous electron transfer and electron transport theories in electrochem. environment. Specific cases of nanobiodevices involving redox metalloproteins are reported and exptl. results are interpreted and discussed in view of the most recent theor. advancements, in order to provide the reader with a comprehensive view of the results and promises in this exciting branch of nanotechnol.
    37. 37
      Romero-Muñiz, C.; Ortega, M.; Vilhena, J. G.; Díez-Pérez, I.; Cuevas, J. C.; Pérez, R.; Zotti, L. A. Ab initio electronic structure calculations of entire blue copper azurins. Phys. Chem. Chem. Phys. 2018, 20, 30392– 30402,  DOI: 10.1039/C8CP06862C
      37
      Ab initio electronic structure calculations of entire blue copper azurins
      Romero-Muniz, Carlos; Ortega, Maria; Vilhena, J. G.; Diez-Perez, I.; Cuevas, Juan Carlos; Perez, Ruben; Zotti, Linda A.
      Physical Chemistry Chemical Physics (2018), 20 (48), 30392-30402CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
      We present a theor. study of the blue-copper azurin extd. from Pseudomonas aeruginosa and several of its single amino acid mutants. For the 1st time, we consider the whole structure of this kind of protein rather than limiting our anal. to the copper complex only. This was accomplished by combining fully ab initio calcns. based on DFT with at.-scale mol. dynamics simulations. Beyond the main features arising from the copper complex, our study revealed the role played by the peripheral parts of the proteins. In particular, we found that oxygen atoms belonging to carboxyl groups which are distributed all over the protein contributed to electronic states near the HOMO. The contribution of the outer regions to the electronic structure of azurins had so far been overlooked. The results highlight the need to investigate them thoroughly; this is esp. important in prospect of understanding complex processes such as electronic transport through metal-metalloprotein-metal junctions.
    38. 38
      Zotti, L. A.; Bürkle, M.; Pauly, F.; Lee, W.; Kim, K.; Jeong, W.; Asai, Y.; Reddy, P.; Cuevas, J. C. Heat dissipation and its relation to thermopower in single-molecule junctions. New J. Phys. 2014, 16, 015004,  DOI: 10.1088/1367-2630/16/1/015004
      38
      Heat dissipation and its relation to thermopower in single-molecule junctions
      Zotti, L. A.; Burkle, M.; Pauly, F.; Lee, W.; Kim, K.; Jeong, W.; Asai, Y.; Reddy, P.; Cuevas, J. C.
      New Journal of Physics (2014), 16 (Jan.), 015004/1-015004/25, 25 pp.CODEN: NJOPFM; ISSN:1367-2630. (IOP Publishing Ltd.)
      Motivated by recent expts., we present here a detailed theor. anal. of the joule heating in current-carrying single-mol. junctions. By combining the Landauer approach for quantum transport with ab initio calcns., we show how the heating in the electrodes of a mol. junction is detd. by its electronic structure. In particular, we show that in general heat is not equally dissipated in both electrodes of the junction and it depends on the bias polarity (or equivalently on the current direction). These heating asymmetries are intimately related to the thermopower of the junction as both these quantities are governed by very similar principles. We illustrate these ideas by analyzing single-mol. junctions based on benzene derivs. with different anchoring groups. The close relation between heat dissipation and thermopower provides general strategies for exploring fundamental phenomena such as the Peltier effect or the impact of quantum interference effects on the joule heating of mol. transport junctions.
    39. 39
      Cascella, M.; Magistrato, A.; Tavernelli, I.; Carloni, P.; Rothlisberger, U. Role of protein frame and solvent for the redox properties of azurin from Pseudomonas aeruginosa. Proc. Natl. Acad. Sci. U.S.A 2006, 103, 19641– 19646,  DOI: 10.1073/pnas.0607890103
      39
      Role of protein frame and solvent for the redox properties of azurin from Pseudomonas aeruginosa
      Cascella, Michele; Magistrato, Alessandra; Tavernelli, Ivano; Carloni, Paolo; Rothlisberger, Ursula
      Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (52), 19641-19646CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      We have coupled hybrid quantum mechanics (d. functional theory; Car-Parrinello)/mol. mechanics mol. dynamics simulations to a grand-canonical scheme, to calc. the in situ redox potential of the Cu2+ + - → Cu+ half reaction in azurin from Pseudomonas aeruginosa. An accurate description at atomistic level of the environment surrounding the metal-binding site and finite-temp. fluctuations of the protein structure are both essential for a correct quant. description of the electronic properties of this system. We report a redox potential shift with respect to copper in water of 0.2 eV (exptl. 0.16 eV) and a reorganization free energy λ = 0.76 eV (exptl. 0.6-0.8 eV). The electrostatic field of the protein plays a crucial role in fine tuning the redox potential and detg. the structure of the solvent. The inner-sphere contribution to the reorganization energy is negligible. The overall small value is mainly due to solvent rearrangement at the protein surface.
    40. 40
      Corni, S. The reorganization energy of azurin in bulk solution and in the electrochemical scanning tunneling microscopy setup. J. Phys. Chem. B 2005, 109, 3423– 3430,  DOI: 10.1021/jp0459920
      40
      The Reorganization Energy of Azurin in Bulk Solution and in the Electrochemical Scanning Tunneling Microscopy Setup
      Corni, Stefano
      Journal of Physical Chemistry B (2005), 109 (8), 3423-3430CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
      The total reorganization energy λ of azurin is theor. studied both for the electron self-exchange reaction and for the protein in the electrochem. scanning tunneling microscopy (ECSTM) setup. The results demonstrate the importance of the proximity between the active sites in the encounter complex to reduce λ for the electron self-exchange reaction and quantifies the effects of the presence of an STM environment (tip and substrate) on λ. A comparison of the calcd. results with exptl. data is performed, and the relative magnitudes of the inner and outer contributions to λ are discussed.
    41. 41
      Kontkanen, O. V.; Biriukov, D.; Futera, Z. Applicability of perturbed matrix method for charge transfer studies at bio/metallic interfaces: A case of azurin. Phys. Chem. Chem. Phys. 2023, 25, 12479– 12489,  DOI: 10.1039/D3CP00197K
      41
      Applicability of perturbed matrix method for charge transfer studies at bio/metallic interfaces: a case of azurin
      Kontkanen, Outi Vilhelmiina; Biriukov, Denys; Futera, Zdenek
      Physical Chemistry Chemical Physics (2023), 25 (17), 12479-12489CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
      As the field of nanoelectronics based on biomols. such as peptides and proteins rapidly grows, there is a need for robust computational methods able to reliably predict charge transfer properties at bio/metallic interfaces. Traditionally, hybrid quantum-mech./mol.-mech. techniques are employed for systems where the electron hopping transfer mechanism is applicable to det. phys. parameters controlling the thermodn. and kinetics of charge transfer processes. However, these approaches are limited by a relatively high computational cost when extensive sampling of a configurational space is required, like in the case of soft biomatter. For these applications, semi-empirical approaches such as the perturbed matrix method (PMM) have been developed and successfully used to study charge-transfer processes in biomols. Here, we explore the performance of PMM on prototypical redox-active protein azurin in various environments, from soln. to vacuum interfaces with gold surfaces and protein junction. We systematically benchmarked the robustness and convergence of the method with respect to the quantum-center size, size of the Hamiltonian, no. of samples, and level of theory. We show that PMM can adequately capture all the trends assocd. with the structural and electronic changes related to azurin oxidn. at bio/metallic interfaces.
    42. 42
      Artés, J. M.; López-Martínez, M.; Giraudet, A.; Díez-Pérez, I.; Sanz, F.; Gorostiza, P. Current-voltage characteristics and transition voltage spectroscopy of individual redox proteins. J. Am. Chem. Soc. 2012, 134, 20218– 20221,  DOI: 10.1021/ja3080242
      42
      Current-Voltage Characteristics and Transition Voltage Spectroscopy of Individual Redox Proteins
      Artes, Juan M.; Lopez-Martinez, Montserrat; Giraudet, Arnaud; Diez-Perez, Ismael; Sanz, Fausto; Gorostiza, Pau
      Journal of the American Chemical Society (2012), 134 (50), 20218-20221CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Understanding how mol. conductance depends on voltage is essential for characterizing mol. electronics devices. We reproducibly measured current-voltage characteristics of individual redox-active proteins by scanning tunneling microscopy under potentiostatic control in both tunneling and wired configurations. From these results, transition voltage spectroscopy (TVS) data for individual redox mols. can be calcd. and analyzed statistically, adding a new dimension to conductance measurements. The transition voltage (TV) is discussed in terms of the two-step electron transfer (ET) mechanism. Azurin displays the lowest transition voltage measured to date (0.4 V), consistent with the previously reported distance decay factor. This low transition voltage may be advantageous for fabricating and operating mol. electronic devices for different applications. Our measurements show that transition voltage spectroscopy is a helpful tool for single-mol. ET measurements and suggest a mechanism for gating of electron transfer between partner redox proteins.

  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jpclett.3c02702.

    • Theoretical details for an N-site hopping model (S1); the role of the protein–electrode coupling in the asymmetry of the IV curves; (S2) dependency of hopping rates on the bias voltage (S3); dependency of hopping currents on reorganization-energy values (S4); and temperature dependence for different reorganization-energy values (S5) (PDF)


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