Frequency dependence of catalyzed reactions in a weak oscillating field

Baldwin Robertson and R. Dean Astumian

National Institute of Standards and Technology, Gaithersburg, Maryland 20899
(Received 14 January 199 1; accepted 11 February 199 1)
The frequency dependence of the average rates of reactions catalyzed by one or more catalysts
in a weak oscillating field is derived. The average rates are sums of Lorentzian curves whose
characteristic frequencies are the inverse relaxation times of the normal modes of the kinetic
system and whose amplitudes are quadratic in the field. The signs of the Lorentz amplitudes
can be either positive or negative, so the rates versus frequency can have a variety of shapes,
including frequency windows. One can get relaxation times and amplitudes by measuring
steady-state rates as a function of the frequency of the field. The theory is applied to determine
the Lorentz amplitudes and characteristic frequencies of ion transport rates catalyzed by Na+-
Kf-ATPase in erythrocytes.
INTRODUCTION
Relaxation kineticsle5 is concerned with the response of
a system of chemical reactions to an external disturbance.
This perturbation of the chemical system from a steady state
can be a change in concentration of one or more reactants or
products, or it can be a change in a thermodynamic param-
eter, which affects one or more rate coefficients. The linear
response to a step function change is a sum of exponentials
whose amplitudes and inverse time constants are those ofthe
normal modes of the system. An equivalent approach is to
apply an oscillating perturbation and measure one or more
oscillating concentrations as a function of frequency.6 The
amplitude of the oscillation is a sum of Lorentzian curves
whose amplitudes and frequencies are those of the normal
modes. This oscillatory response is the Laplace transform of
the transient response.7y8 Another alternative is to measure
the power absorbed by the system. This also is a sum of
Lorentzians, one for each normal mode, but the Lorentz
amplitudes are quadratic in the perturbation.
In this paper we focus on the steady-state rate of a cata-
lyzed reaction in an oscillating field., We show that the
average rate as a function of frequency is also a sum of Lor-
entz curves, whose characteristic frequencies are the inverse
decay times of the normal modes, and whose amplitudes can
be calculated from the kinetic parameters of the system.
Thus information about the elementary kinetic parameters
of a catalytic process can be obtained by measuring the
steady-state rate versus frequency.
We apply this theory to the ac-electric-field-induced
transport of ions through the plasma membrane of erythro-
cytes by Na+-K +-ATPase.*2 The electric field effect
arises because the enzyme has electric charges that move
when it undergoes a conformational change during its cata-
lytic cycle. The effect is large for transmembrane proteins
because the applied electric field results in a lo3 or lo4 times
larger field in the membrane, because the membrane pre-
vents the protein from rotating and thereby evading the ef-
fect of the field, and because the conformational changes of
many membrane proteins involve large displacement
charge.13
CHEMICAL SYSTEM IN AN OSCILLATING FIELD
Consider a system of chemical reactions catalyzed by
one or more enzymes. The kinetic equations for this system
are
dE,/dt = - i (k,Ei - k,iEj),
i = l,...,n,
(1)
j= 1
where the E, are enzyme-state probabilities, n is the number
of enzyme states, and the k, are rate coefficients (with
k,, ~0). Substrate and product concentrations are assumed
to vary slowly. They are not written explicitly here but have
been absorbed into the rate coefficients for brevity. If there is
more than one enzyme, the E, are to be interpreted as prod-
ucts of the individual enzyme probabilities. Since the Ei are
probabilities,
&El = l,
(2)
which can be used to eliminate E,, in favor of the other E,.
When this is done, Eqs. ( 1) may be written as
dE/dt+PE=Q,
(3) *
where E is an (n - 1 )-dimensional column vector whose ith
element is E,, where Q is an (n - 1 )-dimensional column
vector whose ith element is kni, and where P is the
(n - 1) X (n - 1) relaxation matrix, whose ith diagonal
element is
k,i + i kij
,= I
(4)
and whose off-diagonal element in the ith row andjth col-
umn is
kni - kj, .
(5)
An explicit example is given in Appendix A for a four-state
system.
When an electric potential $ is applied, the equilibrium
constant K, in the absence of the potential must be replaced
by
K,> = K, exp(q,$/RT), (6)
7414 J.Chem.Phys.Q4(11),1 June1991 0021-9606/91/117414-06$03.00 @ 1991 Americanlnstituteof Physics
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B. Robertson and R. D. Astumian: Catalyzed reactions in an oscillating field
REACTION RATE where q,, ( = - q,i ) is the electric charge that moves across
the potential Jt during the i toj transition. Alternatively, the
exponent could be the scalar product of the electric field
times the change in electric dipole moment during the i toj
transition, or the pressure times a volume change, etc.
The equilibrium constant K I; is the ratio k ;/kb, so the
effect of the field must be apportioned between the two rate
coefficients. When this is done and an oscillating potential
$4 = Ij, cos(wt)
(7)
is applied, the rate coefficients k, in P and Q are replaced
with
k; = k, exp[zU cos(wt)],
(8)
where z,, = ai,qti@, /RT and ati ( = 1 - aii> is the appor-
tionment constant.
SOLUTION
Since the rate coefficients vary periodically, the matrix
P can be expanded in a Fourier series
P = PO + 2P cos(wt) + *. *
(9)
with
The rate of the transition from state i to statej is
Jo = k ;Ei - k;,E,,
(16)
where i andj are not equal and take the values 1,2,...,n. This
can be written
Jg = R,E + SO,
(17)
where R, is an (n - 1 )-dimensional row vector and S, is a
number defined as follows. There are three cases. If neither i
norj equals n, then the elements of R, are all zero, except the
ith element is k ; and thejth element is - kk, and
S, = 0, i, j#n. (18)
If either i orj equals n, use Eq. (2) to eliminate E, from Eq.
( 16). The elements of R, all equal k Ai, except the ith ele-
mentisk:,, +kLi,and
Sin = -k;,,.
(19)
The elements of R, all equal - k nj except thejth element is
- kj,, - k L,, and
P, =F, P, = Pcos(wt) ,...) (10)
where the overbar denotes an average over one period of the
applied field. Similar equations apply for the column vector
Q. These quantities are easily calculable in terms of modified
Bessel functions.14 The result is that the matrix PO is the
same as P except that k J is replaced by
S,,j = k :, .
(20)
An explicit example is given in Appendix A for a four-state
system.
kj,o = kijI0 (Zg 1, (11)
and P, is the same as P except that k > is replaced by
The average of Eq. ( 17) over a cycle is
$ = R,oA, + R,, A, + S,,, (21)
where the subscripts 0 and 1 mean that R, and S, are com-
posed using expressions ( 11) and ( 12)) respectively, in place
of k ;. When Eqs. (15) and ( 14) are substituted into this, it
reduces to
k,,., = &I, (zti 1. (12)
Similar replacements apply to Q,, and Q, . In this paper we
expand in powers of z and keep terms to second order. Thus
the modified Bessel function in Eq. ( 11) may be approxi-
mated by lo(z) =: 1 +,?/4, and that in Eq. (12) by
I, (z) -,z/2.
3, =I; +xq
pi
Pi +a2
Y, (22)
where
Since P and Q are periodic, the solution E, after any
initial transients have decayed, will also be periodic with the
same period and so can be expanded in a Fourier series
E=& +A, cosot+B, sin&+--.,
(13)
where the coefficients are to be calculated. The value of the
in-phase first-harmonic coefficient is
57 = R,,P, Q. + S,,o
(23)
is the rate of the i to j transition at infinite frequency,
xii =R,, - R,,P;- P,
(24)
is an (n - 1 )-dimensional row vector, and
Y =2Po-(Q, -P,P,Qo) (25)
is an (n - 1 )-dimensional column vector, which equals A,
at zero frequency. Special cases of these equations are dis-
cussed in Appendix B.
A, = 2(P: + w2) - P, (Q, - P, PO Q, 1, (14)
correct to first order in $, . It is proportional to $, and is the
in-phase linear response from relaxation kinetics.14 The
average of the A, term in Eq. ( 13) over a cycle is of course
zero. The average of the state probability isI
NORMAL MODES
Equation (22) leads immediately to the principal result
of this paper. In general the eigenvalues of PO are distinct, so
PO can be diagonalized. I6 Then the i to j transition rate re-
duces to
A, =P;'(Qo -P,A,), (15)
correct to second order in 3,. The oscillating field causes a
change in the average state probability, which could be mea-
sured, e.g., by binding a fluorescent indicator to the enzyme.
The effect on the average state probability contributes to the
average rate of the catalyzed reaction, as shown in the next
section.
where l/?-k is the k th eigenvalue of PO, and where the numer-
ator is the product of the two numbers
Xij,k
= XiiUk
(27)
and
7415
(26)
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Yk = VkY. (28)
Here rk and yk are the relaxation time and the forcing func-
tion of the k th normal mode of the system, the uk are the
column eigenvectors of the matrix P,, , and the vk are the row
eigenvectors.
The frequency-dependent part of the rate (26) is a sum
of Lorentz curves with amplitudes xijkyk. Since both x~,~
and yk are proportional to $, , the amplitudes of the Lorentz
curves are proportional to 6.
Equations (ll), (12), (24), (25), (27),and (28) deter-
mine the Lorentz amplitudes from the kinetic parameters k,
and zii. Numerical routines are available that calculate the
real and/or complex eigenvalues l/r, and column eigenvec-
tors uk of a real general matrix such as P,, . The row eigenvec-
tors are obtained by inverting the matrix whose k th column
is uk. The k th row of the inverse matrix is the row vector vk .
The normalization of the eigenvectors does not affect
the Lorentz amplitudes. Proof: Compute the inverse of the
product of the matrix of column eigenvectors times a diag-
onal matrix whose diagonal elements are not zero. Thus
multiplying a uk by a nonzero constant results in the corre-
sponding vk being divided by the same constant, and the
Lorentz amplitude is not changed.
If the eigenvalues are ordered and l/r, ( l/r, + , for
some m, then in the frequency interval l/r,,, 40 Q l/r, + ,
the rate (26) is constant. If one eigenvalue is small and all
the rest are large, then, in the intermediate frequency inter-
val, the rate (26) reaches a plateau whose height is given by a
Michaelis-Menten expression.
COMPARISON WITH EXPERIMENT
Equation (26) says that the average rates as a function
of frequency are sums of Lorentz curves. Since the individual
Lorentz amplitudes can be either positive or negative, the
curves can combine to form a peak as shown in Fig. 1. A
similar frequency dependence has been observed experimen-
tally.
Tsong and co-workers ,I2 have used radiotracer meth-
ods to measure unidirectional ion transport catalyzed by
Na +-K + -ATPase in erythrocytes as a function of an ap-
plied oscillating electric field. They show that a 20 V/cm (O-
pk) external field (8 mV oscillating membrane potential)
causes net influx of Rb + (an analog of K + ) and net efflux
of Na + . Their data as a function of frequency can be fit by
our theory, thereby determining the amplitudes and relaxa-
tion times of the Lorentz curves.
At first, we fit a sum of two Lorentzians to the Na +
efflux data and independently fit a sum of three Lorentzians
to the Rb + influx data and found that one of the characteris-
tic frequencies from the first fit coincided within 1% with
one of the frequencies from the second fit. We can not say
whether the closeness of the two characteristic frequencies
occurs because a normal mode is shared by the Na+ and
Rb+ transport processes or is only a coincidence. It does
suggest that just four characteristic frequencies with two
nonzero amplitudes for the Na + efflux and three nonzero
amplitudes for the Rb + influx could equally well be fit si-
7416 B. Robertson and Ft. D. Astumian: Catalyzed reactions in an oscillating field
j==;;;---------._
\
\
\
\
\
\
\
\
\
\
\
\
\
a
\
\
2
\
\
\
P/
\
\
\
\
\
.\
\
\
'\
I
'-.
10 IO2 IO3
Frequency
FIG. 1. The solid curve is a typical curve of reaction rate vs frequency. It is
the difference between two Lorentzians. which are the dashed curves.
multaneously to both sets of data. The results of this simulta-
neous fit are reported in Table I and Fig. 2.
In relaxation kinetics, determining relaxation times and
amplitudes unambiguously is difficult when the relaxation
times are close to each other. The same is true here. For
example, the first two modes of Rb + transport are poorly
determined, while the highest mode for Rb + is well deter-
mined because it is isolated.
A kinetic scheme can be compared with experiment by
first fitting the Lorentz curves to the experimental data and
then fitting the kinetic parameters to the Lorentz parameters
using the formulas of the previous four sections. We apply
this technique to Na + -K + -ATPase, simplifying the prob-
lem by considering the Rb + influx separately from the Na +
efflux. The simplest model capable of fitting the Rb + data is
a four-state model, which is described in Appendix A.
Given the Lorentz parameters for just the one experi-
ment,12 there is not enough information to determine
uniquely the kinetic parameters for Rb + influx catalyzed by
Na + -K + -ATPase. Additional measurements are neces-
sary, e.g., for different substrate and product concentrations,
etc. However, one example of kinetic parameters that give
the Lorentz parameters of Table I appears in Table II. Other
kinetic parameters exist that would do just as well. Thus only
guarded conclusions about Na + -K + -ATPase can be
drawn from Table II. The values are presented only to illus-
trate what kind of information can be obtained using our
method.
TABLE I. Lorentz parameters for Na+ and Rb+ transport by Nat-K+-
ATPase in erythrocytes.
k 1 2 3 4
1/27-n-, (ms-) 0.564 0.601 186 4290
71 (p(s) 282 265 0.855 0.0371
Rb+: (amol/RBC/hr) xIyI - 278.2 272.4 7.24 0
Na + : (amol/RBC/hr) xI yI 0 0 - 35.80 32.05
J. Chem. Phys., Vol. 94, No. 11,l June 1991
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P
AZ
3
2
.
b
E
2.
3
=
c
+
e
f
Jz
ii
CT
\
5
ii
5
E
+
2
B. Robertson and R. D. Astumian: Catalyzed reactions in an oscillating field
7417
30,
25-
20-
15-
IO-
0'
1 I I I I I I
I
012345678
Log (Freq. in Hz)
60
50
40
30
20
10
03
012345678
Log (Freq. in Hz)
FIG. 2. Theoretical frequency dependence of membrane transport flux
compared with experiment. The upper curve is a sum of three Lorentzians
and the lower curve is a sum of two Lorentzians, with one characteristic
frequency common to the two curves. These curves are fitted simultaneous-
ly to Rb + and Na + flux measurements from Ref. 12. The best-fit param-
eters are given in Table I. The bars on the data points represent one standard
deviation uncertainty. There is only one experimental point that deviates
much from the theoretical curve, and it is within 1.7 standard deviations.
POWER
The reaction rate can change sign as a function of fre-
quency,8*9 even for a nonelectrogenic catalyzed reaction.
When the flux is uphill, the energy for this must come from
thefield.6,0.3.0
In this section, we derive expressions for the
frequency dependence of the chemical and electrical power.
TABLE II. Example ofkinetic parameters that give the Lorentz parameters
for Rb in Table I.
ij
12 2,3 394 4,1
% 0 - 0.0339 0 0.0539
5 0 0.0339 0 - 0.0539
k,,(ms-) 2.45 568 1.36 0.616
k,,(ms-) 1.26 600 2.27 0.681
4 1.94 0.947 0.600 0.905
The power supplied by the applied field is the time aver-
age of the voltage times the electric current
9
e,ec = &+ cosW>Jg, (29)
where we have normalized by dividing by RT. Insert Eq:
( 17) into this and do the average over a cycle to get
9
elec =+@(Ri& ++R,,A, +&I.
This can be evaluated as before to yield
(30)
where
9:
elec
=fp(R,J,P, +s,,,,
the x,k are numbers given by
X
e.k = + &?jRty,o%,
(33)
(31)
(32)
and the yk are the same numbers as before. Equation (3 1)
for the electrical power has the same sum-of-Lorentzians
form as Eq. (26) for the rate. We expect the Lorentz ampli-
tudes for the electric power all to be negative so the power
increases monotonically with frequency.
The chemical power output is
9 them
= pJP
(34)
wherepu,,, is the chemical potential of the ligand for the i toj
transition. This expression can be evaluated using Eq. (26)
to get
(35)
where
9
them = c lug; (36)
ifi
is the chemical power at infinite frequency, the x,,~ are
numbers satisfying
xcvk = ;/hvxij,k,
(37)
and the yk are the same as before. Equation (35) for the
chemical power output has the same sum-of-Lorentzians
form as Eqs. (26) and ( 3 1) for rate and electrical power.
SUMMARY
This paper shows that the average rates of a catalyzed
reaction versus the frequency of an applied oscillating field
are sums of Lorentz curves, and it gives a systematic proce-
dure for calculating the Lorentz amplitudes and frequencies
from the kinetic parameters of the chemical system. This
provides a general method for determining kinetic param-
eters by measuring the steady-state rate of a catalyzed reac-
tion as a function of the frequency.
The Lorentz amplitudes of the reaction rates can be ei-
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7418 B. Robertson and R. D. Astumian: Catalyzed reactions in an oscillating field
ther positive or negative. This makes frequency windows
possible, in agreement with experiment. The theory is not
limited to the catalyzed reaction being near equilibrium. At
steady states very far from equilibrium, the Lorentz ampli-
tudes and frequencies may be complex, although they always
appear in complex-conjugate pairs so that the sum is real.
ACKNOWLEDGMENT
We thank Dr. Jeffrey Sachs for reading the manuscript.
APPENDIX A: FOUR-STATE SYSTEM
We write some expressions explicitly for the four-state
system
k
23 \
2
k
EIL
32
jr J
k
21
k k
43 34
12
k L
14
El,
k
E, 43
41
(Al)
The time-dependent relaxation matrix for this system is
[
k;, + k;, + k;, k;, -k;,
k
P=
-k;, k;, +k;,
-ii;, ,
k
43 k;3 -k;,
k;, +k;, +k;,
1
(A21
the time-dependent inhomogeneous term is
k
Q= ; ,
[ I
(A31
k
43
and the expressions used to calculate the reaction rates are
R,, = [k;,, -k;,, O-J, S,, =O,
R,, = [O, k;,, -k;,], s2, =O,
R,, = [k;,, k;,, k;, +k;,], S,, = -k;j, (A41
R,, = [ -k;,-k;,, -k;,, -k;,], S,, =k;,.
The time-dependent rate coefficients in all of these expres-
sions are given by Eq. (8). The matrices PO and P, , the
column vectors Q. and Q, , the row vectors R, and R, , and
the numbers S, and S, are obtained from Eqs. (A2)-( A4)
by replacing the k I; in these equations with k,, and k,,
using Eqs. ( 11) and ( 12), respectively.
Because the four-state scheme is a single cycle, the aver-
age reaction rates for the four transitions must equal each
other and equal the rate of the catalyzed reaction. This rate
can be calculated using Eqs. (23)-(28).
APPENDIX B: SPECIAL CASES
Substantial simplification occurs for perturbations
about equilibrium. For nonelectrogenic catalyzed reactions,
y depends only on equilibrium constants, the chemical pow-
er is zero, and at zero frequency the electrical power and all
rates are zero. On the other hand, the rates at infinite fre-
quency are zero provided the apportionment constants equal
l/2.
Since y equals A, at zero frequency, it is straightforward
using Eqs. ( 3)) (7)) and ( 13 ) to show that y is $, times the
derivative of P - Q with respect to $. At equilibrium,
P - Q depends only on the field-dependent equilibrium
constants. For nonelectrogenic catalyzed reactions, the sys-
tem remains in equilibrium when perturbed at zero frequen-
cy. Thus in this case y depends only on equilibrium con-
stants.
The average rate at zero frequency can be calculated as
follows. For a nonelectrogenic catalyzed reaction at equilib-
rium, the instantaneous rates remain zero throughout the
cycle, and so the average rates at zero frequency are zero.
This can be used to eliminate the rate at infinite frequency
from Eq. (26), which then reduces to
Xij,kYk . (Bl)
A similar result is obtained for the electric power.
Equation (23) for the average rate at infinite frequency
can also be derived from Eq. (2 1) by observing that at infi-
nite frequency A, and B, are zero so that E is just A,, which
is Pop Q,, . Equation (23) is the same as the usual result for
steady-state rate in the absence of the oscillating field* ex-
cept that the rate coefficients k, are multiplied by I, (zti).
When the unperturbed catalyzed reaction (electrogenic or
not) is at equilibrium, only ratios of these rate coefficients
appear in P; Q, , and I0 cancels out of the ratios when the
apportionment constants for nonzero q. are all l/2. Then
the rates at infinite frequency are all zero.
APPENDIX C: NARROWEST PEAK
The characteristic frequencies and amplitudes of the
Lorentzians in Eq. (26) are real numbers except very far
from equilibrium. Here we discuss the dependence on fre-
quency.
The difference of two Lorentzians of equal amplitude
J=
JO JO
1 tf/fi - 1 tf/f:
forms a peak with a maximum at frequency
(Cl
f = cfifi ,*=AJ. (C2 ,I
In terms of the maximum rate
J
max = JOG -f, l/v; +.A 1,
the rate (Cl ) reduces to
cc31
J=
u-i +f,n-
C./y +f,v: +f, Jmax*
The full width at half amplitude of this peak is
(C4)
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B. Robertson and R. D. Astumian: Catalyzed reactions in an oscillating field
7419
cc51
If we let the characteristic frequencies f, and f2 approach
each other while holding f. and J,,,,, constant, JO increases,
and the peak narrows, except that Af remains larger than its
limiting value 2fo. The effect of bringing the two frequencies
together while holding JO constant merely reduces the am-
plitude (C3) of the peak.
When the eigenvalues and Lorentz amplitudes are com-
plex, the rates are sums of complex-conjugate pairs and
hence are real. If the real part of the eigenvalue were small
compared with the imaginary part, the sum would take a
resonance form22*23 with a narrow width. But if, as we expect
for a linear system such as ( 1 ), the imaginary part of the
eigenvalues and Lorentz amplitudes are not larger than their
real parts,24 the sum is at least as broad a function of fre-
quency as Eq. (C4). A conclusion is that the bandwidth is
not narrowed by driving a linear system far from equilibri-
um. This is important in interpreting the minimum detect-
able perturbation in the presence of thermal noise.25
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