J. Phys. Chem.

B 2007, 111, 2747-2751 2747

Improved Whitten-Rabinovitch Approximation for the Rice-Ramsperger-Kassel-Marcus

Calculation of Unimolecular Reaction Rate Constants for Proteins

Meiling Sun,† Jeong Hee Moon,‡ and Myung Soo Kim*,†

Department of Chemistry, Seoul National UniVersity, Seoul 151-742, Korea, and Korea Research Institute of
Bioscience and Biotechnology, Daejon 305-806, Korea
ReceiVed: October 2, 2006; In Final Form: January 16, 2007

The Whitten-Rabinovitch (WR) approximation used in the semi-classical calculation of the Rice-
Ramsperger-Kassel-Marcus (RRKM) unimolecular reaction rate constant was improved for reliable
application to protein reactions. The state sum data for the 10-mer of each amino acid calculated by the
accurate Beyer-Swinehart (BS) algorithm were used to obtain the residue-specific correction functions (w).
The correction functions were obtained down to a much lower internal energy range than reported in the
original work, and the cubic, rather than quadratic, polynomial was used for data fitting. For a specified
sequence of amino acid residues in a protein, an average was made over these functions to obtain the sequence-
specific correction function to be used in the rate constant calculation. Reliability of the improved method
was tested for dissociation of various peptides and proteins. Even at low internal energies corresponding to
the RRKM rate constant as small as 0.1 s-1, the rate constant calculated by the present method differed from
the accurate BS result by 60% only. In contrast, the result from the original WR calculation differed from the
accurate result by a factor of 3000. Compared to the BS method, which is difficult to use for proteins, the
main advantage of the present method is that the RRKM rate constant can be calculated instantly regardless
of the protein mass.

I. Introduction
In the study of a unimolecular reaction, it is often useful to
have a rate constant evaluated theoretically. For a unimolecular
reaction occurring under the microcanonical condition, the
Rice-Ramsperger-Kassel-Marcus (RRKM) theory1-6 is widely
used to estimate the statistically expected rate constant. The
theoretical rate constant is useful not only for direct comparison
with the experimental one but also for various other purposes.
For example, RRKM calculation is done in the field of mass
spectrometry7-9 as an aid for understanding the structure and
dissociation dynamics of molecular ions, estimating their internal
energy contents, etc.
When the molecular rotation is ignored, the expression for a
unimolecular reaction rate constant derived by the RRKM theory
is as follows.
Nq(E - E0)
k)σ (1)
hF(E)
Here F(E) is the vibrational state density of the reactant at
the internal energy E, E0 is the critical energy of the reaction,
Nq(E - E0) is the vibrational state sum from 0 to E - E0 at the
transition state (TS), h is the Planck constant, and σ is the
reaction path degeneracy, which is usually 1 for reactions
involving large molecules.
Even though the expression for the RRKM rate constant looks
deceptively simple, various difficulties are encountered in actual
calculation. The parameters needed for a RRKM calculation
* To whom correspondence should be addressed. Telephone: +82-2-
880-6652. Fax: +82-2-889-1568. E-mail: myungsoo@snu.ac.kr.
† Seoul National University.
‡ Korea Research Institute of Bioscience and Biotechnology.
10.1021/jp066453t CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/15/2007
are the critical energy, the complete vibrational frequency set
for the reactant, and that at the TS geometry. The major
difficulty arises from the fact that the parameters related to the
TS, namely E0 and the frequencies at the TS, cannot be
measured experimentally. The data obtained via quantum
chemical calculations can be used when the TS can be found
through computation. The less rigorous but more widely used
approach is to treat these as adjustable parameters. It is well-
known that the RRKM rate constant remains nearly the same
regardless of the changes in individual frequencies as long as
the entropy of activation, ∆Sq, is kept the same.7,10-12 Hence,
the RRKM calculation of the rate-energy relation is often
treated as a two parameter (E0 and ∆Sq) problem. In this
approach, the frequency set at the TS is obtained from the
reactant set by adjusting some of the frequencies in the latter
set such that the postulated value of ∆Sq results. The fact that
reasonable estimates for E0 and ∆Sq are needed for reliable
estimation of the rate constant is the main drawback of this
approach.
When one attempts a RRKM calculation for large biological
molecules such as peptides and proteins, additional difficulties
arise due to the very large number of degrees of freedom
involved. One of these difficulties is that it is virtually impossible
at the moment to obtain the complete set of reactant frequencies
either via experiment or via computation. In our previous
paper,13 we reported a systematic and efficient method to
estimate the frequency set for a peptide or a protein with any
amino acid sequence and presented its utility in a RRKM
calculation. The method started with the vibrational frequency
sets for twenty amino acids calculated at the density functional
theory (DFT) level. Then, the frequencies disappearing upon
peptide bond formation were deleted from each set to obtain
the fictitious sets for an amino acid residue at the N- or
2748 J. Phys. Chem. B, Vol. 111, No. 10, 2007
C-terminus or inside the chain. For a specified sequence of a
protein, these residue frequencies were collected and the
frequencies appearing upon peptide bond formation were added
to obtain the complete set for the reactant. The frequencies
appearing upon protonation of a protein were added as needed
to handle the reaction of protonated proteins that are of great
interest in the field of mass spectrometry.14-16 The method
treated all the vibrations as harmonic and ignored anharmonicity.
Also ignored was the fact that some modes are better treated as
internal rotations rather than vibrations.1,5 Such simplifications
and the estimation of the frequencies at the TS using the
postulated value of ∆Sq adopted in this method are causes for
uncertainty in the RRKM calculations.
Once the frequency sets for the reactant and TS are provided,
various methods can be used to calculate the vibrational state
sum and density. Several approximate methods had been
developed in early days of RRKM calculations such as the
Whitten-Rabinovitch (WR) semi-classical approximation17 and
the steepest descent method18 to name a few. Even though these
methods are efficient, all of these provide erroneous results at
low internal energy range.1 For example, Derrick et al.19 showed
that the WR method overestimated the dissociation rate constant
of a small protein by orders of magnitude in the low internal
energy. Virtually all of these approximate methods became
obsolete after the invention of an efficient direct counting
algorithm by Beyer and Swinehart (BS algorithm).20 When we
attempted the RRKM calculation for proteins with relative
molecular masses (RMM) as large as 10 000 or larger using
the BS algorithm, however, we found that several hours or even
days of computation were needed.
In this paper, we will present a modification of the Whitten-
Rabinovitch method for proteins. Its reliability in RRKM
calculation for proteins will be demonstrated by comparing with
the results obtained by the BS algorithm.
II. Method
In the Whitten-Rabinovitch (WR) approximation,17 the fol-
lowing expression is used for the vibrational state sum as
suggested by Rabinovitch and Diesen.21
(E + aEz)s
N(E) ) (2)
s!∏hνi
Here E is the vibrational internal energy as before, Ez is the
zero-point energy, s is the number of the vibrational degrees of
freedom, and νi is the frequency of the ith vibrational mode.
This expression differs from the original semi-classical expres-
sion suggested by Marcus and Rice2 in that the parameter a is
regarded as a molecule-dependent function of the internal energy
rather than a constant (a ) 1) in the latter expression. To reduce
the molecule dependence in the calculation, Whitten and
Rabinovitch suggested to use another function w defined as
below.
w ) (1 - a)/β (3)
with
s - 1 〈ν 〉
2
β) (4)
s 〈ν〉2
By comparing with the state sums for various organic and
inorganic molecules calculated by direct count, Whitten and
Rabinovitch obtained the following expression for w.
Sun et al.
w ) (5.00 + 2.730.5 + 3.51)-1 0.1 <  < 1.0 (5)
w ) exp(-2.41910.25) 1.0 e  (6)
Here,  is the internal energy scaled with the zero-point
energy.
 ) E/Ez (7)
The expression for the state density is obtained from the
derivative of eq 2 as follows.
(E + aEz)s-1
F(E) )
(s - 1)! ∏ hνi
[1 - β(dwd )] (8)
Because both the sum and density are expressed in explicit
analytical forms, the rate constant is calculated instantly as the
frequencies and E0 are provided.
As has been mentioned already, the rate constant calculated
by the WR method deviates significantly from the direct count
result in the low internal energy range. It is well-known in the
field of mass spectrometry that the critical energies for many
dissociation reactions of peptide and protein ions are rather
low.22-24 Such an ion may dissociate on the mass spectrometric
time scale (1 µs to 1 s) even when the internal energy is only
a few electronvolts above the critical energy. Because the zero-
point energy increases in proportion to the reactant mass, a few
electronvolts of internal energy correspond to  less than 0.1,
which is below the limit optimized by Whitten and Rabinovitch.
Also to be mentioned is that the w data used to derive the
functions in eqs 5 and 6 in the original work showed a
significant scatter even at  larger than 0.1 because these were
the values obtained for compounds with widely different
structures.17 The corresponding scatter is expected to be smaller
when only the data for peptides and proteins are taken into
account. The method used to calculate the RRKM rate constant
for proteins in this work is essentially the same as in the original
WR method. The only difference is that the sequence-specific
w function derived from peptide data is used in the present work.
Details of the method are as follows.
The state sum for a 10-mer, X10, of each amino acid was
calculated with the BS algorithm as a function of  in the range
 ) 0.0005-2. Then, the w data for each peptide were calculated
using eqs 2-4. These were taken as the representative data for
this amino acid residue because the w data obtained from higher
polymers were essentially the same. These data were used to
obtain the w function of the following form.
w ) (c31.5 + c2 + c10.5 + c0)-1 (9)
The first term in this function was added to achieve fits with
the correlation coefficient better than 0.99999. Two improved
WR methods, IWR′ and IWR, were developed and tested. In
the IWR′ method, a universal w function for proteins was
estimated by averaging the w functions of the 10-mers of twenty
amino acids using the natural abundances25 of the amino acids
as the weighting factors. In the IWR method, the ci parameters
for each amino acid residue in a protein were collected and
averaged term by term, for example, C3 ) 〈c3〉, to estimate the
w function for this protein. Namely, the w function used in the
latter method differed for proteins with different amino acid
composition unlike in the former method. It will be shown in
the next section that IWR is our method of choice. The function
in eq 6 turned out to be an excellent fit to the w data at  > 1
Improved WR Approximation for Proteins J. Phys. Chem. B, Vol. 111, No. 10, 2007 2749

Figure 1. The w functions for the 10-mers of twenty amino acids

obtained by comparing the vibrational state sums calculated by the BS Figure 2. The rate-energy relations for M10 calculated by the BS
algorithm with eq 2. The w functions for M10 and T10 are marked, which (s), WR (- ‚ -), IWR′ (-O-), and IWR (----) methods using an E0
form the upper and lower boundaries of the data, respectively. Also of 0.5 eV and a ∆Sq of 0 eu.
drawn is the w function in the original Whitten-Rabinovitch ap-
proximation. The abscissa is the internal energy scaled by the zero-
point energy. TABLE 1: List of the c Parameters Derived from the
10-mers of Twenty Amino Acids
for all the cases investigated even though calculations above  c3 c2 c1 c0
) 1 were hardly needed in practical cases. Ala(A) 0.763603 3.422871 3.911022 3.166518
Details of the method to calculate a rate-energy relation for Cys(C) 0.831468 3.203076 4.014916 3.201546
a protein reaction with the BS algorithm were explained in a Asp(D) 1.138528 2.643839 4.308187 3.206942
Glu(E) 1.329782 2.226432 4.641321 3.068151
previous report13 and will not be repeated here. For the improved Phe(F) 1.236776 2.461058 4.385026 3.152760
Whitten-Rabinovitch (IWR) calculation, the array (c3, c2, c1, Gly(G) 1.095241 2.802168 4.215922 3.150475
c0) for each amino acid residue has been stored in the software His(H) 1.347598 2.266191 4.474229 3.176003
together with the residue frequencies. When the amino acid Ile(I) 0.919614 3.068504 4.184229 3.044556
sequence of the reactant is specified, the residue frequencies Lys(K) 1.128924 2.624142 4.441859 3.012481
are collected and the w function is calculated from the arrays. Leu(L) 1.039792 2.839106 4.299746 3.024606
Met(M) 1.215631 2.452458 4.548003 2.988617
The frequencies at the TS are estimated from the reactant Asn(N) 1.262370 2.378021 4.448872 3.149506
frequencies and ∆Sq, which is designated by a user as one of Pro(P) 1.349337 2.226658 4.544044 3.083142
the input parameters of the software. These and the E0 value Gln(Q) 1.222632 2.460278 4.463422 3.080824
are used to calculate F(E) and Nq(E - E0) and finally k(E). Arg(R) 1.305170 2.346235 4.582904 3.021681
Ser(S) 1.067582 2.816962 4.217357 3.166776
Thr(T) 0.886543 3.266588 3.900925 3.215289
III. Results and Discussion
Val(V) 0.881758 3.171401 4.115937 3.068043
The inverse cubic fittings of the w data were made for the Trp(W) 1.285702 2.468111 4.353988 3.194517
10-mers of twenty amino acids as described in the previous Tyr(Y) 1.222054 2.492761 4.348006 3.185401
section. The 0.001 e  e 1.0 ranges of the twenty w functions
thus obtained are shown in Figure 1 together with the original significant at this energy, and that the rate constant is quite large
w function drawn with eq 5. The w data at  > 1.0 are not even at such a low internal energy. As expected from the larger
shown because eq 6 is an excellent description in this range deviation of the correct w data from eq 5 at lower energy as
regardless of the peptides. Two w functions, namely those for seen in Figure 1, the WR rate constant in Figure 2 differs more
the 10-mers of methionine (M10) and threonine (T10), are marked from the BS rate constant at lower internal energy. When an
in the figure. As the internal energy decreases, the peptide w ion cyclotron resonance mass spectrometer is used, the dis-
data begin to deviate more and more from eq 5. Deviation is sociation of a protein ion occurring on the time scale as long
the largest for M10, and it is the smallest for T10. The (c3, c2, c1, as 10 s may be observed, even though canonical rate constants
c0) arrays determined for the twenty 10-mers through curve rather than microcanonical ones calculated in this work may
fitting are listed in Table 1. be more appropriate in some cases. Hence, let us compare the
Figure 2 compares the rate-energy relations for M10 calcu- rate constants at the internal energy corresponding to the BS
lated by various methods using an E0 of 0.5 eV and ∆Sq of 0 rate constant of 0.1 s-1 from now on. In the present case, this
eu (1 eu ) 4.184 J K-1 mol-1). The zero-point energy for this occurs at 1.38 eV. At this energy, the WR rate constant is as
peptide calculated with the reactant frequencies used in the rate large as 300 s-1, corresponding to a factor of 3000 difference
calculation is 39.6 eV. Hence, the internal energy of 3.96 eV is from the correct result. It is evident that the original WR method
equivalent to the scaled energy () of 0.1. The rate constant cannot provide a reasonable estimate of a rate constant at  <
calculated with the BS algorithm at this energy is 1.48 × 106 0.1, even though physically meaningful reactions may occur at
sec-1, corresponding to the half-life of 0.48 µs. On the other such a low internal energy. To summarize, the WR method is
hand, the rate constant calculated by the original WR method rapid but inaccurate in the low-energy range and the BS method
is 5.79 × 106 s-1, which is larger than the correct (BS) value is accurate but slow in the high-energy range. A way to get out
by a factor of 3.9. Such a difference is understandable because of this dilemma may be to calculate the rate-energy relations
the correct w value for M10 at this energy is 0.2121, which is a using both methods, the BS calculation in the low-energy range
little larger than the 0.2052 calculated by eq 5. It is to be and the WR calculation over the entire energy range of interest,
emphasized that  ) 0.1 was the lower limit for the internal and use the two together. Certainly, a better way is to devise a
energy in the derivation of the w function in the original work, unified method that is efficient and accurate at the same time,
that the discrepancy between the WR and BS rate constants is as attempted in the present work.
2750 J. Phys. Chem. B, Vol. 111, No. 10, 2007
Initially, we hoped to achieve the above goal by using a
universal w function that could be used for proteins with any
sequence. The IWR′ method described in the previous section
was devised for this purpose. The rate-energy relations
calculated by the IWR′ method were in excellent agreement
with the BS results for many peptides consisting of a variety of
amino acid residues. In the IWR′ calculations, the largest error
is expected for the peptides consisting of only one type of amino
acid residue, especially M10 and T10. The rate-energy relation
for M10 calculated by the IWR′ method with an E0 of 0.5 eV
and a ∆Sq of 0 eu is shown in Figure 2 also. The IWR′ rate
constant is in much better agreement with the BS result than is
the WR result. At the internal energy of 1.38 eV chosen in the
previous comparison, the IWR′ rate constant is 1.3 s-1,
corresponding to a factor of 13 difference from the correct value.
Namely, the difference factor of 3000 in the original WR method
has been reduced to 13 in IWR′. We are not satisfied with the
IWR′ method, however, because our aim is to develop a method
that can reproduce a BS rate constant within a factor of 2.
As has been mentioned already in the previous section, our
method of choice (IWR) is to calculate a sequence-specific w
function by averaging the w functions (w-1 actually) of the
residues contained in a protein. The rate-energy relation for
M10 calculated by IWR using the same E0 and ∆Sq values as
before is also shown in Figure 2. Because all the residues are
the same in M10, the sequence-specific w function evaluated
from the residue functions is exactly the same as the residue
function that was derived using the state sum calculated by the
BS algorithm. Hence, one may expect to obtain an IWR rate
constant that is essentially identical to the BS result. Even though
the IWR and BS rate-energy relations in Figure 2 are nearly
the same, a tiny difference can be observed. For example, the
IWR rate constant at 1.38 eV is 0.160, namely 60% larger than
the BS result. To see if the functional fitting of the w data is
the source of such an error, we calculated the state density at
1.38 eV using the w function and compared it with the BS state
density. The BS density turned out to be larger than the IWR
density only by 0.2%, which is the fitting error for the state
density. We also calculated the state sum at 0.88 eV, which is
the internal energy at the TS. Here, the difference between the
IWR and BS results was only 7% when the reactant frequencies
were used. Hence, it is unlikely that the fitting error is the main
source for the 60% error in the rate constant. The main error in
the present IWR method may arise from the fact that the
vibrational frequencies at the TS are different from the reactant
frequencies that are used to obtain the w function. To check
such a possibility, we carried out RRKM calculations for M10
with the same E0 but increasing ∆Sq to 10 eu, which is a typical
value for a loose transition state5 reaction. Here again, the rate-
energy data calculated by IWR were much better than those by
WR, even though the deviation from the BS results was larger
than in the E0 ) 0.5 eV and ∆Sq ) 0 eu case, as expected. The
rate constant in the 0.1 s-1 range differed by a factor of 6. The
RRKM calculations were done with an E0 of 1.0 eV and a ∆Sq
of 10 eu also. Here, the IWR and BS results were in excellent
agreement as in the E0 ) 0.5 eV and ∆Sq ) 0 eu case.
The RRKM calculations were done for peptides consisting
of various amino acids also. These included well-known peptides
such as angiotensin I (DRVYIHPFHL, monoisotopic relative
molecular mass (RMM) of 1295.7) and 100 randomly generated
peptides consisting of ten amino acid residues. We also carried
out calculations for various fictitious proteins such as the
fictitious 8-mer of angiotensin I, (DRVYIHPFHL)8, with a
monoisotopic RMM of 10 239.4 to check the reliability of the
Sun et al.
present IWR method for higher mass proteins. The general trend
in all these cases was the same as in the M10 case: overestima-
tion of k near 0.1 s-1 by 60-80% in the calculations with E0 )
0.5 eV and ∆Sq ) 0 eu and overestimation by a factor of 6
with E0 ) 0.5 eV and ∆Sq ) 10 eu.
From the results presented so far, it is obvious that a rate-
energy relation calculated by the IWR method reproduces the
corresponding BS result satisfactorily except when E0 is small
and ∆Sq is large at the same time. In the present work, the
vibrational frequency set at the TS is estimated by adjusting
some of the frequencies of the reactant such that the postulated
∆Sq results. As ∆Sq gets larger, these adjusted frequencies get
smaller. Then, the state sum evaluated using the w function
derived with the reactant frequency data deviates more from
the correct value, resulting in larger deviation in the rate
constant. When E0 gets larger also, the agreement between the
IWR and BS results gets better even when ∆Sq is large. The
explanation for the better agreement at larger E0 is as follows.
As E0 increases, the rate constant at a given internal energy
decreases rapidly. In fact, the internal energy needed to maintain
the rate constant at the same value, and hence the internal energy
at the TS also, increases almost in proportion to E0. At high
internal energy, however, the influence of the above low-
frequency vibrations at the TS becomes less important, resulting
in better agreement between the IWR and BS rate constants.
Even though the present IWR method is not adequate to
reproduce the BS rate-energy relation for a simultaneously
small E0 and large ∆Sq case such as E0 ) 0.5 eV and ∆Sq ) 10
eu, it is to be mentioned that such a case is unlikely to be
encountered in protein dissociations. In dissociation reactions,
a large value of ∆Sq, or the occurrence of a loose transition
state,5 is usually associated with simple bond cleavage reactions,
which tend to have a large E0 value. It is well-known in the
field of mass spectrometry that the b and y type fragment ions
are generated preferentially when the internal energy of a
protonated peptide is not high,26 which indicates that they are
generated via reaction paths with small E0 values. According
to the DFT calculation for the dissociation of [G3 + H]+ carried
out by Paizs and Suhai,22 generation of the b2 ion occurred with
the smallest value of E0 (0.42 eV) and dominated in the low
internal energy range. The value of ∆Sq evaluated using the
frequencies at the reactant and TS geometries supplied by Paizs
and Suhai was -2.65 eu. This is in agreement with our
speculation that there is probably no dissociation channel with
simultaneously small E0 and large ∆Sq values for protein ions.
If such a channel existed, it would have dominated the fragment
ion spectra over the entire internal energy range. However, it is
known26 that the major fragment ion types in the dissociation
of peptide and small protein ions change from b and y to a, d,
v, w, and x as the internal energy increases. Absence of reaction
channels with simultaneously small E0 and large ∆Sq values
means that the IWR method developed in this work is probably
reliable for dissociation of protein ions. Without attached
protons, the critical energy for the dissociation of a neutral
protein will be probably larger than the corresponding value
for the protonated form.
The forgoing discussion on the influence of entropy on the
accuracy of the IWR method has arisen because the w function
derived with the reactant frequencies in this work is not quite
adequate at the TS. A related problem may arise from the fact
that the reactant frequencies used in this work are those
estimated for linear peptides and proteins. The frequencies of a
protein may be affected by hydrogen bonding even in the gas
phase. Then, the w function derived in this work may be invalid
Improved WR Approximation for Proteins
to deal with the dissociation of gas-phase proteins, rendering
the present method useless. Out of this concern, we attempted
some primitive calculations for peptides with intramolecular
hydrogen bonding. For this purpose, we assumed that the
frequencies affected by hydrogen bonding are those of the N-H
and CdO stretching modes. Then, the frequencies of these
modes in the set stored for each amino acid residue was reduced
by 5% based on the spectral correlation appearing in the
literature.27 The rate-energy relations thus obtained were hardly
distinguishable from the original data, suggesting that the w
function derived by the present method can be used even when
intramolecular hydrogen bonding is present in a protein.
Finally, we compared the rate-energy relations calculated
with E0 ) 0.5 eV and ∆Sq ) 0 eu for the monomer, 8-mer, and
80-mer of angiotensin I. The internal energies corresponding
to, for example, 103 s-1 in these molecules were 1.97, 14.21,
and 140.01 eV, respectively, increasing nearly in proportion to
the molecular mass. This is in agreement with our previous
suggestion28 that the internal energy needed to observe a
particular type of protein reaction with the same rate constant
increases almost in proportion to the number of degrees of
freedom, which, in turn, is almost proportional to the molecular
mass of proteins. Because the zero-point energies of proteins
increase almost in proportion to the molecular mass also, 42.18,
332.77, and 3321.73 eV for the monomer, 8-mer, and 80-mer,
respectively, the three rate-energy curves can be brought into
near coincidence by drawing them with the scaled energy in
the abscissa.
IV. Conclusion
Even though the BS algorithm is efficient and accurate in
evaluating the vibrational state sum and density needed in the
RRKM calculation of a unimolecular reaction, its application
to biopolymers is limited because the computational time
increases rapidly with the molecular mass. In this work, the
WR approximation used in the semi-classical calculation of a
rate constant has been improved such that the rate constant for
a unimolecular reaction of a protein evaluated by this method
closely reproduces the BS result. Its main advantage lies in the
fact that a rate constant can be calculated instantly regardless
of the protein mass. It has been found that the rate constant
calculated by this method differs from the BS result significantly
for reactions occurring with simultaneously small E0 and large
∆Sq values. Certainly, it is a weakness of the present method
even though such a situation is unlikely to be encountered in
actual protein dissociations. Another weakness of the present
approach is that the method is valid only for peptides and
proteins. Completely new functions must be derived for other
J. Phys. Chem. B, Vol. 111, No. 10, 2007 2751
biopolymers such as nucleic acids and carbohydrates, even
though the method to derive such functions would be the same
as in this work. In this regard, it may be worthwhile to
investigate other approximate methods developed previously
such that an efficient and accurate method with general
applicability to any biopolymer can be established.
Acknowledgment. Meiling Sun thanks the Ministry of
Education for the Brain Korea 21 fellowship. The software
developed in this work will be made freely available.
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