Microelectronic Circuit Analogous to Hydrogen Bonding Network in Active Site of -lactamase

Short Paper
ACEEE Int. J. on Signal and Image Processing , Vol. 5, No. 1, January 2014

Microelectronic Circuit Analogous to Hydrogen
Bonding Network in Active Site of -lactamase
Rostislav P. Rusev1, Elitsa E. Gieva2, George V. Angelov2, Rossen I. Radonov2, and Marin H. Hristov2
1

Technical University of Sofia/Department of Technology and Management of Communication Systems,
Sofia, Bulgaria
Email: rusev@ecad.tu-sofia.bg
2
Technical University of Sofia/Department of Microelectronics, Sofia, Bulgaria
Email: {gieva, gva, radonov, mhristov}@ecad.tu-sofia.bg

structurally engineered proteins and theoretical analysis of
the results led to the formulation of a comprehensive paradigm
for electron and proton transport in proteins [8].
In our previous research [9, 10, 11, 12, 13] we have
investigated information transfer through hydrogen bonding
networks of the -lactamase protein. After extraction of protein
hydrogen bonding networks (HBNs) from the enzyme
periphery, we have investigated the charge transport. We
have matched each residue (from protein HBN) to functionally
analogous block-element to describe the proton transfer with
polynomials. Next, static and dynamic analyses have been
performed on the circuits consisting of block-elements. The
simulation results are compared to conventional
microelectronic circuits.
In this paper we focus on information transfer via protein
hydrogen bonding networks and their operation as analogs
to conventional electronic circuits. In particular, we
investigate HBNs formed in the active site of the -lactamase
protein.

Abstract—A microelectronic circuit of block-elements
functionally analogous to two hydrogen bonding networks is
investigated. The hydrogen bonding networks are extracted
from â-lactamase protein and are formed in its active site.
Each hydrogen bond of the network is described in equivalent
electrical circuit by three or four-terminal block-element.
Each block-element is coded in Matlab. Static and dynamic
analyses are performed. The resultant microelectronic circuit
analogous to the hydrogen bonding network operates as
current mirror, sine pulse source, triangular pulse source as
well as signal modulator.
Index Terms—Hydrogen bonding network, behavioral
modeling, Matlab, Verilog-A, proteins.

I. INTRODUCTION
Bioelectronics is dynamically evolving part of electronics.
The integration of biomolecules with electronic elements to
yield functional devices attracts substantial research efforts
because of the basic fundamental scientific questions and
the potential practical applications of the systems. A
fundamental requirement of any bioelectronics system is the
existence of electronic coupling and communication between
the biomolecules and the electronic supports [1]. The
understanding of charge transport phenomena through
biological matrices attracted in the past decades, and
continues to evolve, intensive theoretical and experimental
work. The seminal contributions of the Marcus theory [2],
the super exchange charge transfer theory [3], and the
definition of superior tunneling paths in proteins [4] had a
tremendous impact on the understanding of biological
processes such as the electron transfer in the photosynthetic
reaction center, or the charge transport in redox-proteins that
are the key reactions for numerous electrochemical and
photoelectrochemical biosensing systems.
The small dimensions of the bioobjects make them
appropriate for various types of biosensors [5], pH-sensors
[6], light sensors [7], etc. A biosensor is generally defined as
an analytical device which converts a biological response
into a quantifiable and processable signal. A continuous
feedback between elegant experimental work employing

II. MODEL AND EQUATIONS
The two hydrogen bonding networks formed at the active site during the four intermediates of acyl-enzyme reaction are shown in Fig.1; they are denoted “nucleophilic” and
“electrophilic”. Proton transfer in each hydrogen bonding
network was studied in [14]. In the paper is introduced proton transfer parameter K (in accordance with the constant of
the electron transfer). It has dimension of free energy, and
from the calculations it can be interpreted as follows: the
greater parameter K - so much readily accomplished proton
transfer between donor and acceptor from HBNs, i.e. the proton current will be greater. On the other hand the parameter
of proton transfer depends on the donor/acceptor potentials
similarly to the potentials supplying the microelectronic components. Therefore we can construct three and four-terminal
electronic block-elements analogous to the hydrogen bonds.
During the four intermediates of the half-cycle of the acylenzyme reaction participate the same residues and water
molecules. For this reason the corresponding microelectronic
block-elements in the equivalent electrical circuits are the
same but they are connected in different way. Therefore, two
functionally analogous microelectronic circuits for the four
intermediates of acyl-reaction are constructed; the circuits

The research is related to the project No BG051PO001-3.3.06-0046
“Development support of PhD students, postdoctoral resea rchers
and young scientists in the field of virtual engineering and industrial
technologies”., corresponding author: Elitsa Gieva

© 2014 ACEEE
DOI: 01.IJSIP.5.1.1450

93

Short Paper

Figure 1. Acyl-enzyme reaction intermediates – HBNs in the active site of: (E) free enzyme, (ES) Michaelis complex, (T1) t ransient state,
(EY) acylenzyme. The first HBN is referred to as “nucleophilic” consists of residue S70, water molec ule w297, residues N170, E166, K173,
N132 and ligand. The second referred to as “electrophilic” consists of consists of residues S130, K2 34, water molecule w309, and residues
D214, S235

depend on switch S that corresponds to the ligand. In this
paper we will analyze one intermediate of the acyl-reaction
only, i.e. the free enzyme (state (E) in Fig.1) without a ligand.
In Fig.2 it is shown the microelectronic circuit analogous
to HBNs formed in the active site of lactamase.

juxtaposed to S70OG residue, which is a three terminal blockelement with identical input and output voltage and different
input and output currents.
In the circuit of Fig. 2 the water molecule w297 is compared
to block-element T3. It should be noted that depending on
the state of the switch S, block-element T3 changes its
function. In this case T3 has two inputs and one output.
The block-element T4 is functionally analogous to E166,
which is strong proton acceptor and can form different
hydrogen bonds. T4 block-element is represented as a three
terminal block-element with one input and one output. The
other two block-elements T5 and T6 are similar to asparagines
N132 and N170. Asparagine could be both proton-donor and
proton-acceptors in the circuit, therefore N132 and N170 can
change the direction of the currents as a depending on the
switch S.
The input of the second circuit on Fig. 2 is labeled with
Uin2. This electrical circuit is functionally analogous to the
“electrophilic” hydrogen bonding network, which also has
three outputs. Here block-element T10 is also a voltage
controlled current source and it corresponds to the strong
proton-donor K234NZ. In this block-element (similarly to T1)
the two output voltages are identical to the input voltage but
the input and output currents are different. The next blockelement T11 is analogous to the water molecule w309. In
state (E) the element has two inputs and one output. The
residue D214 is juxtaposed to block-elements T12; T12 has

Figure 2. Microelectronic circuit analogous to HBNs formed in the
active site of
lactamase when
lactamase is free enzyme
(state E)

The input voltage of the first electric circuit analogous to
“nucleophilic” hydrogen bonding network is labeled as
“Uin1”. Block-element T1 corresponds to lysine K73NZ. The
lysine is a strong proton donor, so in the circuit it is interpreted
as a voltage controlled current source. Block-element T2 is
© 2014 ACEEE
DOI: 01.IJSIP.5.1.1450

94

Short Paper
one input and one output, and the T12 output is also the
circuit output. The three terminal block-element T13 is
compared to S130OG. Its input and output voltages are
identical, but the input-output currents are different. The
block-element T14 is the last output block-element of the
integrated circuit. It is functionally analogous to S235OG and
has the same functions as S130OG (respectively T13).
It should be noted that there is proton transport in both
HBNs during the different intermediates of the reaction. The
proton transport is influenced by pH and protein-ligand
interaction. In this reason, both electrical circuits are not
separated from each other (similar to an integrated circuit)
and the input voltages of both units are equal in analogy of
pH.
The model equations that describe the electrical relations
of the each block-element are given below.
Equations (1) and (2) describe the T1 block-element.
U1 = Uin;
-5

3
1

-5

2
1

I11 = 2×10-5×U113 -13×10-6×U112 -0.00015×U11
+0.00048;
U12 = 0.9683×U11 +0.458;
I12 = I11;
U13 = 1.1009×U10 -0.3571;
I13 = 10-5×U134 +2×10-5×U133 -8×10-5U132 +2×10-5× U13
+0.0015;

(1)

U14 = 1.034×U11 -0.1986;

-5

I1 = 3×10 U – 5×10 U -7×10 U1 + 0.0013;

I14 = 0×U14 +0.0001;


The equations are coded in Matlab [15]. Excerpt of the
code is given below.

U2 = 1.0451×U1 – 0.1194;
I2 = – 0.0236×U23 + 0.0379×U22 + 0.124×U2 +1.3046;

U2 = 1.0451*U1 -0.1194;
plot(U1,U2,’linewidth’,2);
set(gca,’fontweight’,’b’,’fontsize’,14)
grid on
title(‘T2’);
xlabel(‘Uin [V]’);
ylabel(‘U2 [V]’);
legend(‘simulation’,’data’);
set(legend(‘simulation’,’data’,1),’fontsize’,12);
pause;
I2 = - 0.0236*U2.^3 + 0.0379*U2.^2 + 0.124*U2 +1.3046;
load(‘bsy1_e.dat’);
U2exp = bsy1_e(:,3);
I2exp = bsy1_e(:,4);
plot(U2,I2,U2exp,I2exp,’ro’,’linewidth’,2);
set(gca,’fontweight’,’b’,’fontsize’,14)
grid on
title(‘T2’);
xlabel(‘U2 [V]’);
ylabel(‘I2 [pA]’);
% legend(‘simulation’,’data’);
set(legend(‘simulation’,’data’,1),’fontsize’,12);
pause;

U3 = 1.0179×U2 – 0.039
I3 = 0.0015×U33 – 0.0015×U32 -0.0171×U3 + 0.0859;
Equations (7) and (8) describe block-element T4.
U4 = 0.9703×U3 +0.0589
I4 = I3 = Iout1;
U5 = 0.0457×U12 +1.2273×U1 – 0.8501;
I5 = 0×U5 +0.0001;
U6 = 1.0544×U3 – 0.0933;
I6 = 0.0058×U62 + 0.0367×U6 + 0.7113;

III. STATIC ANALYSIS

U10 = 0.9701×U1 + 0.2072;

Static analysis is performed in Matlab. First, we tested
how well our polynomial I-V characteristics describe the components and connections between them. In Fig. 3 are shown
the compared results from simulations and the previous data
for block elements T1 and T2.
As it can be seen from Fig. 3, the polynomials well describe
the functional dependencies of the modeled block elements.

I10 = 4×10-5×U104 – 6×10-5×U103 – 0.0002×U102 +
0.0004×U10 + 0.00252;
U11 = 0.9835×U10 +0.1438;
© 2014 ACEEE
DOI: 01.IJSIP.5.1.1450

95

Short Paper
The I-V characteristic of first output is similar to I-V
characteristic of tunnel diode [9].
In Fig. 5 the output voltages are shown.

a)

Figure 5. The output voltages vs. input voltage.

The output voltages repeat the form of the input voltage.
This is also observed in our previous paper for HBNs in the
periphery of -lactamase protein [9].
In Fig. 6 the current of the second output is shown.

b)
Figure 3. I-V characteristic of block elements a) Ò1 and b) Ò2
(emulating Ê73, S70)

Similar results were seen for the other block elements of the
circuit (by this reason they are not shown), and the maximum
calculated error is 5.66%.
After the comparative analysis between the simulations
and the data taken from [14], a static analysis is made for the
entire integrated biocircuit. The results for each output of
the circuit are shown below. Fig. 4 shows the I-V characteristics of output 1.

Figure 6. I-V characteristic of second output current.

Current does not change with the change of voltage (its
value is 0.0001 [pA]). Therefore, this output has
characteristics similar to a current source as observed in [10,
11].
In Fig. 7 the current of the third output is shown.
For case E current increases according to an exponential
law with increasing voltage and output characteristic is similar
to shifted characteristics of diode.
Fig. 8 shows the current characteristic on output 12.
Current is amended by S-shaped law.
At the next output (13) there is a curve which is a
combination of the curves of S-shape (Fig. 9).
At the next output 14 (Fig. 10) the current does not
change by changing the voltage.
Characteristics are similar to the current generator (Fig.
10), as it was for output 2 [12].
From the standpoint of its mode of use, the circuit could

Figure 4. I-V characteristic of first output current

© 2014 ACEEE
DOI: 01.IJSIP.5.1.1450

96

Short Paper

Figure 7. I-V characteristic of third output current

Figure 10. I-V characteristic of fourteenth output current

circuit with multiple output; therefore, a thorough dynamic
analysis is required. To understand in detail its mode of action,
research were made when applying three types of sinusoidal
voltages at the input. First was applied voltage with an
amplitude from -2.2 to 2.2 [V] (Fig. 11) and the frequency of 10
[GHz] then was applied voltage with the same frequency, but
only the positive or only the negative amplitudes and sweep
of 1 [V]. These simulations showed that the output voltage
repeats the input voltage in form and frequency, and the
amplitude is on the same order.

Figure 8. I-V characteristic of twelfth output current

Figure11. The input voltage vs. time Uin = 2.2*sin((5e11)*t)

This behavior was expected because from static analysis
we know that the output voltages are shifted off the input
voltage by linear law. Therefore, for convenience we will
present only the input voltage and output currents vs. time.
For output currents again we see that they keep their positive amplitude regardless whether voltages are in negative or
positive half-period. As an example, in Fig. 12 we showed
voltage and current on output 1, input voltage is with amplitude from -2.2 to +2.2 [V]. If input voltage with positive amplitude is applied (Fig. 13, 14) different signal amplitude sinusoidal signals are generated at output 1; the currents are
shifted in relation to the voltages.

Figure 9. I-V characteristic of thirteenth output current

be used as a current generator or as an amplifier. Further its
capabilities will be demonstrated in the dynamic analysis.
IV. DYNAMIC ANALYSIS
The integrated circuit functionally similar to hydrogen
bonding networks in the active site of the protein is a complex
© 2014 ACEEE
DOI: 01.IJSIP.5.1.1450

97

Short Paper

Figure 14. The first output current vs. time (Uin =1,5
+0.5*sin((5e11)*t))

Figure12. The voltage and current on first output vs. time (Uin =
2.2*sin((5 e1 1)*t
Figure 15. The input voltage vs. time Uin = -1+0.5sin((5e11)*t)

Figure 13. The input voltage vs. time Uin =1,5 +0.5*sin((5e11)*t)

When applied a input voltage with negative amplitude
(Fig. 15) for output 1, we obtain the modulated signal with
the same phase for current (Fig. 16). Similar phenomena was
observed in our previous paper [13].
Simulations show that the second output current does
not change (Fig. 17) when applying with different amplitude
(and frequency) input voltages.
This output is similar to the output of the current-mirror,
© 2014 ACEEE
DOI: 01.IJSIP.5.1.1450

Figure 16. The first output current vs. time Uin = 1+0.5 sin((5e1 1)*t)

i.e. the currents not dependent on a change of the voltage,
as determined by the static analysis.
When applying a sinusoidal voltage with a positive amplitude (Fig.15) the output 3 starts to generate sinusoidal
signals (Fig. 18).
The same output signals are obtained when applying the
98

Short Paper

Figure 17. The second output current vs. time

Figure 19. The output current on output 12 vs. time (Uin =
2.2*sin((5 e11 )*t))

Figure 18. The third output current vs. time (Uin = 1,5
+0.5sin((5e11 )*t))

Figure 20. Other types of signals generated on output 12.

the input voltage (Fig. 23): the currents are constant (0.0001
[pA]) and the output behaves similarly to the current-mirror
or current source.
The results of the dynamic analysis showed that the
integrated circuit functionally analogous to the hydrogen
bonding network in the active site of the protein -lactamase
could operate in different modes and to generate different
types of signals and can also modulate the different in
amplitude and shape signals.

sinusoidal input voltage with negative amplitude. Therefore
they are not shown in any figures.
The most complicated generated signals are obtained at
the output 12. When is applied a sinusoidal input signal with
an amplitude of -2.2 to +2,2 V, then output starts to modulate
(Fig. 19).
When applying an input voltages with only positive or
only negative amplitude, the circuit allows the generation of
other types of signals (triangular) as shown below (Fig. 20).
Generally, only this output of the circuit is able to generate
signals, such as number of previously known in electronic
devices. These signals can be controlled by changing the
amplitude of the input signal.
The situation is similar at output 13 and there is generation
of signals with various shape and amplitude depending on
the amplitude of the input voltage (Fig. 21, 22). The
comparison of the signals at output 13 and output 12 showed
that these signals are different.
Output T13 can easily be put into mode that generates
sinusoidal signals only. This happens when applying the
input voltage with a negative amplitude (Fig. 17).
Here in Fig.22 current is in phase with the input voltage
(respectively the output voltages).
The output current at T14 output does not change with
© 2014 ACEEE
DOI: 01.IJSIP.5.1.1450

2.2*sin((5 e11 )*t))

99

Short Paper
REFERENCES
[1] Prof. Dr. Itamar Willner and Dr. Eugenii Katz, Bioelectronics
– An Introduction (pages 1–13), Online ISBN: 9783527603763,
DOI: 10.1002/352760376X, Copyright © 2005 Wiley-VCH
Verlag GmbH & Co. KGaA
[2] A. Markus, and V. Helms, “Compact parameter set for fast
estimation of proton transfer rates”, J. Phys. Chem, Vol. 114,
pp. 3, 2001.
[3] Bixon, M.; Jortner, J. “Electron Transfer – from Isolated
Molecules to Biomolecules”. Adv. Chem. Phys. 1999, 106,
35-202.
[4] H.B. Gray, J.R. Winkler, Electron tunneling through proteins,
Q. Rev. Biophys. 36 (2003) 341–372.
[5] Prof. Dr. Itamar Willner, Dr. Eugenii Katz, Bioelectronics:
From Theory to Applications, Chapter 12, Published Online:
23 MAY 2005, DOI:10.1002/352760376X.ch12.
[6] Paola Fabbri, Francesco Pilati, Luigi Rovati, Ruel McKenzie,
Jovan Mijovic, Optical Materials, Poly(ethylene oxide)–silica
hybrids entrapping sensitive dyes for biomedical optical pH
sensors: Molecular dynamics and optical response, Optical
Materials 33 (2011) 1362–1369, 2011.
[7] Sudarshan Rajagopal and Keith Moffat, Crystal structure of a
photoactive yellow protein from a sensor histidine kinase:
Conformational variability and signal transduction, 1649-1654
(2002)
[8] H. B. Gray and J. R. Winkler, “Electron Transfer in Proteins”,
Annu. Rev. Biochem. 1996, 65, 537-561.
[9] Gieva, Elitsa E., Characterization of a Hydrogen Bonding
Network in Cadence using Verilog-A, E+E Journal – pp 1824, ‘3-4’ 2012
[10] Elitsa Gieva, Rostislav Rusev, George Angelov, Marin Hristov,
Tihomir Takov, Internation Journal BIOAUTOMATION,
2012, 16(4), pp 291-308, Published: January 8, 2013
[11] Rostislav Rusev, George Angelov, Elitsa Gieva, Marin Hristov,
and Tihomir Takov, Hydrogen Bonding Network Emulating
Frequency Driven Source of Triangular Pulses”, International
Journal of Microelectronics and Computer Science, vol.1, No3,
pp.291-296, 2010
[12] Elitsa Gieva, R. Rusev, G. Angelov, T. Takov, M. Hristov,
“Simulation of Branching Hydrogen Bonding Network in
Cadence”, Proc. of the 1st Intl. Conf. Systems, Power, Control,
Robotics (SCOPORO ’12), pp. 171-176, Singapore City,
Singapore, May 11-13, 2012. ISBN: 978-1-61804-094-7
[13] Elitsa Gieva, Penov L., Rusev R., Angelov G., Hristov M.,
“Protein Hydrogen Bonding Network Electrical Model and
Simulation in Verilog-A”, Annual Journal of ELECTRONICS,
Volume 5, Number 2 pp.132-135, ISSN 1313-1842, Sozopol
14-16 September, 2011
[14] Rostislav Rusev, George Angelov, Elitsa Gieva, Boris
Atanasov, Marin Hristov, Microelectronic Aspects of
Hydrogen Bond Characteristics in Active Site of b-lactamase
during the Acylenzyme Reaction, Annual Journal of
ELECTRONICS, ISSN 1314-0078, Volume 6 , Number 2 ,
pp.35-38, 2012.
[15] Matlab website http://www.mathworks.com.

Figure 22. The input voltage and output current on output 13 vs.
time (Uin = -1.5 +0.5sin((5e11)*t))

2.2*sin((5 e11 )*t))

V. CONCLUSION
The block-elements of the microelectronic circuit well
describe the behavior of the hydrogen bonding network. Static
analysis shows that the circuit could operate as tunnel diode,
current source and multifunctional device. From the results
of the dynamic analysis, it can be seen that the circuit could
operate in different modes and generate in their outputs
different types of signals. The circuit has functions similar to
current-mirror, source of different signals with sinusoidal and
triangular amplitude, and can modulate signals with different
amplitude and shape. The results obtained prove that the
modeled circuit can emulate the behavior of hydrogen
bonding networks for microelectronics applications.
ACKNOWLEDGMENT
The research is related to the project No BG051PO0013.3.06-0046 “Development support of PhD students,
postdoctoral researchers and young scientists in the field of
virtual engineering and industrial technologies”. The project
is implemented with the financial support of the Operational
Programme Human Resources Development, co-financed by
the European Union through the European Social Fund.
© 2014 ACEEE
DOI: 01.IJSIP.5.1.1450

100

Microelectronic Circuit Analogous to Hydrogen Bonding Network in Active Site of -lactamase

More Related Content

What's hot

More from IDES Editor

Recently uploaded

Microelectronic Circuit Analogous to Hydrogen Bonding Network in Active Site of -lactamase