Qiang Cui,
University of Wisconsin
0
=
a
0
. (1)
The different DFTB models are derived by expanding the DFT total energy functional around
this density
0
in rst, second and third orders, respectively. The rst order terms constitute the
standard DFTB1 model, which originally was called simply DFTB,
1,2
while the model based on
the second order expansion, DFTB2, was originally called SCCDFTB.
3
In the last years we have
derived thirdorder terms, leading to the DFTB3
48
model.
If the ground state density is written in terms of the reference density
0
and the density
2
uctuation ,
=
0
+, (2)
the DFTB total energy can be expanded in the respective orders as:
E[] = E
0
[
0
] +E
1
[
0
, ] +E
2
[
0
, ()
2
] +E
3
[
0
, ()
3
]. (3)
E
0
and E
1
constitute the DFTB(1) model, including E
2
denes DFTB2, and the inclusion of E
3
yields the DFTB3 model.
The different DFTB models have reasonably clear areas of application. DFTB1 is suitable for
systems, in which the charge transfer between atoms is small, such as homonuclear systems or
systems with atoms of similar electronegatitvity. Therefore, DFTB1 is well suited for the descrip
tion of hydrocarbons for which the higher order terms are small. On the other hand, DFTB1 can
also treat systems where a complete charge transfer between the atoms occurs, as, for example, in
NaCl.
5
DFTB1 is 510 times faster than DFTB2/DFTB3 since it does not require a selfconsistent
determination of the charge distribution; i.e., it requires a solution of the generalized eigenvalue
problem only once instead of 510 times on average for DFTB2/DFTB3. By contrast, the increase
in CPU time from DFTB2 to DFTB3 is negligible. The second order terms are crucial for polar
molecules, where only partial charge transfer occurs,
5
and the thirdorder expansion becomes in
dispensable for charged molecular species,
6,7
as will be discussed in more detail below. Therefore,
for an application to biological molecules DFTB2 or DFTB3 is required. Since DFTB3 does not
imply any major increase in computational cost, we recently devised a new DFTB3 model by de
riving a parameter set called 3OB, which we recommend to use in standard applications of DFTB
to biological molecules.
8
Three approximations follow the expansion of the total energy in Eq.3: (i) The energy contri
bution E
0
[
0
] is approximated by a sum of pair potentials, which are tted for a set of molecules
to appropriate reference data. (ii) The KohnSham orbitals
i
appearing in the term E
1
[
0
, ]
3
are expanded in a minimal atomic orbital basis
)
rrr rrr

drrrdrrr
_
V
xc
[
0
]
0
(rrr)drrr +E
xc
[
0
] +E
nn
+
i
n
i
H[
0
]
i
_
+
1
2
__
_
1
rrr rrr

+
2
E
xc
[]
(rrr)(rrr
0
_
(rrr)(rrr
)drrrdrrr
+
1
6
_ __
3
E
xc
[]
(rrr)(rrr
)(rrr
0
(rrr)(rrr
)(rrr
)drrrdrrr
drrr
= E
0
[
0
] +E
1
[
0
, ] +E
2
[
0
, ()
2
] +E
3
[
0
, ()
3
].
(4)
Central to the performance of the DFTB models are several approximations following this
expansion, which are:
(i) E
0
[
0
] consists of the DFT double counting contributions and the nuclearnuclear repul
sion in the rst line of Eq.4 and depends only on the reference density
0
, which is given by the
superposition of neutral atomic densities (Eq.1). In other words, this term is not dependent on
the specic chemical environment; it can be determined for an appropriate reference system and
then applied to other molecules. This is the key to the transferability of the derived parameters. In
DFTB, this termis approximated by a sumof pair interactions referred to as the repulsive potential,
E
rep
=
1
2
ab
V
rep
ab
, (5)
(see Ref. 9), which is either determined by comparison to DFT calculations
1
or tted to empirical
data.
12
This approach neglects threebody contributions, which may become important in certain
cases, such as in condensed phase systems.
13
(ii) E
1
consists of the Hamiltonmatrix elements <
i

H
0

i
> in the second line of Eq.4:
H
0
is the KohnSham Hamiltonian of the molecular system but with the reference density.
i
are the KohnSham orbitals, which are represented in a minimal basis of pseudoatomic orbitals,
i
=
c
i
. This is a central part of the computational efciency since it reduces the size of the
5
eigenvalue problem signicantly.
E
1
[
0
, ] =
iab
b
n
i
c
i
c
i
H
0
(6)
where H
0
are the Hamilton matrix elements in the atomic orbital (AO) representation. The diago
nal elements of H
0
a
, in which the spherical atomic
contributions are approximated by a simple Slater function with q
a
= q
a
q
0
a
(q
a
is the Mulliken
charge of atom a and q
0
a
the number of valence electrons of the neutral atom a) centered on the
nucleus at RRR
a
:
a
q
a
3
a
8
e
a
rrrRRR
a

(7)
With this approximation, the Coulomb interaction of the second order term with respect to can
be expressed analytically and is abbreviated as
ab
in the following. The exponent
a
is chosen
such that the onsite value of the function properly describes the atomic chemical hardness (or
alternatively the Hubbard parameter as calculated from DFT) and, therefore, implicitly takes into
account the exchangecorrelation contribution to the second order term. To improve this interpo
6
lation between longrange Coulomb interaction and the onsite term, further renements on the
function have been applied.
7
As discussed in Refs.,
4,5
the derived function
ab
assumes a specic inverse relationship of
the chemical hardness U of an element with its atomic size. Although this relation holds well
within one row of the periodic table, it does not for elements of different rows. In particular,
hydrogen turned out to deserve special attention and we therefore proposed a modied
ab
function
referred to as
h
ab
.
57
This modied function can be applied within DFTB2, but it is not the default
option. Within DFTB3, it has become default
7,8
and therefore is a key ingredient of the DFTB3
methodology.
(iv) The E
3
term consists of diagonal and offdiagonal contributions. Originally, only the
diagonal terms have been included.
46
As in DFTB3, a monopole approximation is applied and this
term describes the change of the chemical hardness of an atom with its charge state.
5
Specically,
in third order a new parameter is introduced, the charge derivative of the chemical hardness, U
d
.
This parameter can be computed fromDFT or optimized in order to improve the performance of the
model. In DFTB3, U
d
contributes at the thirdorder through a function, which is the derivative
of
ab
with respect to atomic charge. It is interesting to note that Giese et al.
18
showed within
the framework of a rigorous densityfunctional expansion method that the thirdorder contribution
does not add signicantly to accuracy, in contrast to our nding with calculations based on diverse
sets of molecules.
68
Therefore, the thirdorder terms in DFTB3 can be seen as a systematic way to
introduce the charge dependence to compensate for deciencies of intrinsic approximations within
the second order formalism, namely, the small size of the pseudoatomic orbital basis, the xed
shape of the initial atomic densities
a
0
as well as the simplied density uctuation scheme.
With all these approximations the DFTB3 total energy is given by
E
dftb3
=
1
2
ab
V
rep
ab
+
iab
b
n
i
c
i
c
i
H
0
+
1
2
ab
q
a
q
b
h
ab
+
1
3
ab
(q
a
)
2
q
b
ab
. (8)
The derivative of this expression with respect to the molecular orbital coefcients, c
i
, leads to the
7
corresponding KohnSham equations
c
i
_
H
i
S
_
= 0 with b and a, a, (9)
H
= H
0
+S
c
q
c
_
1
2
(
ac
+
bc
) +
1
3
(q
a
ac
+q
b
bc
) +
q
c
6
(
ca
+
cb
)
_
, (10)
where S
is the overlap matrix. The Hamilton matrix elements depend on the Mulliken charges,
which in turn depend on the molecular orbital coefcients Thus, these equations have to be solved
selfconsistently.
Dispersion correction
Dispersion interactions play an important role in processes dominated by noncovalent interactions,
such as conformational transitions of biomolecules. In the DFTB framework, the rst attempt
19
to
include dispersion was to augment the DFTB2 energy with an empirical dispersion term, following
the similar strategy applied to HartreeFock energies; the results were promising
19
and stimulated
similar developments for pure DFT methods.
2023
However, due to the use of a minimal basis set of
atomic orbitals, which are slightly compressed with respect to atomic orbitals, the electron density
in DFTB2 is not well described for large distances, especially for the overlap of weakly interacting
densities which are essential to the description of van der Waals (vdW) interactions. The early
parametrization of DFTB2 for organic and biological molecules
2
led to an underestimation of dis
tances in hydrogen and vdW bonded complexes. Therefore, an empirical dispersion correction has
been proposed which also contains a repulsive contribution in order to correct for this artifact.
24
The new DFTB3 parametrization 3OB corrects for this problem by using a slightly more extended
atomic orbital basis set, leading to a good description of noncovalently bonded complexes using
the original dispersion correction from Ref. 19. Recently, Grimme has parametrized his D3
23
cor
rection for DFTB3, leading to an excellent performance of DFTB3D3 for a large set of hydrogen
2
referred to as the mio set, see www.dftb.org
8
and vdW bonded molecules.
25
Treatment of Electron Spin
Standard DFTB is a closedshell method and therefore exhibits large errors for openshell systems.
Khler et al. have formulated an openshell DFTB variant that includes spinpolarization effects
either in a collinear
26,27
or a noncollinear fashion.
28
Besides doubling the orbital set for spin up
and spin down electrons, an additional term is added to the total energy that takes into account the
Mulliken spinpopulation and atomic spinpolarization constants. The latter are calculated from
DFT as numerical difference of partially spinpolarized states in proximity of the spinunpolarized
state of an atom. The collinear spin treatment improves the description of radicals of organic
molecules. However, for some systems the direction of spinquantization varies signicantly in
space (e.g., antiferromagnetism), for which the noncollinear spinpolarization treatment is neces
sary. Note that for the collinear case the amount of computation time doubles with respect to the
nonpolarized calculation, while for the noncollinear one the cost quadruples.
Inherited DFT problems
DFTB is derived from DFT and usually GGA functionals (PBE) are applied to compute the terms
in E
1
, E
2
and E
3
. Since E
0
only affects bond energies but not the electronic spectrum in total, ap
plying higher level methods or experimental data for the determination of E
0
does not compensate
for most of the problems inherent to DFTGGA, except for overbinding, which could be almost
entirely removed in DFTB3/3OB. The deciency of DFTGGA in describing vdW interactions can
be compensated by using empirical dispersion corrections, as describe above. All other phenom
ena related to the selfinteraction problem (SIC) in DFT are retained in the DFTB model. This
is reected, for example, in the performance of DFTB for the subsets of problematic cases in the
GMTKN24
29
test set (SIE11, DARC, DC9), as discussed in Ref. 8. The selfinteraction problem
shows up in many properties and is contained in the second and thirdorder terms in DFTB. A
detailed analysis has been published recently.
30,31
The description of the balance between charge
9
delocalization and polarization, for example in charge transfer complexes, is also a challenge to
DFT. Rapacioli et al.
32
adapted recently a conguration interaction method, based on constrained
DFT calculations, into the DFTB approach. This allows one to investigate charge resonances in
molecular complexes and describe the proper dissociation behavior.
QM/MM coupling
DFTB has been combined with empirical force eld methods in a QM/MM framework as de
scribed in Ref.
33
This scheme has further been extended to include also a continuum electrostatics
environment in the DFTB/MMGSBP scheme,
34
which is useful to the study of chemical reactions
in large macromolecular systems.
35,36
For the interaction between QM and MM atoms, it is common to include both electrostatic
and van der Waals contributions;
3739
bondedterms are also included when the partitioning is
across covalent bonds. In most biomolecular applications, electrostatics tend to dominate and
therefore it is essential that electrostatic interactions between QM and MM atoms are properly
described. For DFTB, the QMMM electrostatic interaction is approximately calculated in the
original implementation
33
as the Coulombic interaction between the QM Mulliken charges (q
a
)
and MM point charges (Q
I
). The error due to this approximation can be signicant when QM
and MM atoms approach each other where charge penetration effect becomes important. As a
result, reactions that involve highly charged solutes/substrates are difcult to study with the original
DFTB/MM Hamiltonian.
40
The problem can be partially solved by enlarging the QM region, but
this introduces not only additional cost but also technical complications for cases that involve
highly mobile solvents, such as the need of changing QM/MM partitioning on the y.
41,42
In our recent work,
43
motivated by the KlopmanOhno (KO) expression for the twocenter two
electron integrals in semiempirical QM methods,
44
which also inspired the development of the
ab
kernel in the original DFTB, we have implemented a different Hamiltonian for the DFTB/MM
10
electrostatics. It takes the form,
H
QM/MM
elec,KO
=
aQM
AMM
q
a
Q
A
_
R
2
aA
+a
a
(
1
U
a
(q
a
)
+
1
U
A
)
2
e
b
a
R
aI
=
aQM
AMM
KO
q
a
Q
A
(11)
in which a
a
and b
a
are element type dependent parameters. Together with the van der Waals
parameters in the QM/MM Hamiltonian, there are 4 QM/MM parameters for each element type,
and they can be determined based on microsolvation clusters.
43
To be consistent with the third
order formulation of SCCDFTB,
7
the Hubbard parameter in the KO functional is dependent on
the QM charge. As a result, the effective size of the QM charge distribution naturally adjusts
as the QM region undergoes chemical transformations, making the KO based QM/MM scheme
particularly attractive for describing chemical reactions in the condensed phase.
Our studies of charged solutes and chemical reactions clearly indicate that the KO scheme
is robust and transferable. For the tting set clusters, both the pointcharge and KO schemes
have comparable errors (relative to full QM results) in solutesolvent interactions, with the Mean
Unsigned Error, (MUE) of 3.3 and 4.8 kcal/mol, respectively (note that the errors are for total
solutesolvent interactions, which are often >100 kcal/mol, thus the error is typically less than
5%!). However, for 16 stable structures and 24 transition states in the QCRNA database, the MUE
is 4.3 kcal/mol for the KO scheme but 16.2 kcal/mol for the pointcharge based QM/MM model.
As another example, for the hydrolysis of phosphate mono esters in solution
43
the hydrolysis
barrier is grossly overestimated ( 11 kcal/mol) with SCCDFTBPR/MM simulations using the
pointcharge based QMMM Hamiltonian.
3
With the KO scheme, the computed barrier is in close
agreement (within 2 kcal/mol) with available experimental data.
Parametrization
The parametrization of the DFTB models involves three steps:
3
SCCDFTBPR is a DFTB variant including only diagonal 3rd order terms and a specic modication and
parametrization for phosphate hydrolysis. See Ref.
40
11
(i) The determination of the parameters for E
1
:
This is usually the rst step in the parametrization. Here, one has to compute
H
0
=<

H[
0
]
> (12)
and S
for setting up the Hamilton Matrix elements in Eq.10. In a rst step, one has to determine
the atomic orbital basis set
, which is called r
0
, the connement radii for the atomic densities
a
0
, which
is called r
d
0
, the atomic Hubbard parameter U
a
and its charge derivative U
d
a
. The determination
5
These parameter sets can be downloaded from the website www.dftb.org.
6
In earlier work applying the diagonal DFTB3 method in combination with the mio set, tted U
d
values com
pensated for the overbinding of the method. This is no longer needed using 3OB since this parametrization removes
the overbinding by changing the density compression radii.
8
Further, the special parametrization and modication for
phosphorous compounds
40
is no longer required due to the introduction of the 3rd order offdiagonal terms.
13
of r
0
and r
d
0
is an empirical procedure and can be quite involved,
8,12
while U
a
and U
d
a
can be
easily computed in principle. For the modied function
h
one additional parameter appears,
which is tted to reproduce the water dimer binding energy. The repulsive potentials are twobody
contributions, therefore they are much more involved although largely automated procedures have
been recently developed.
12
While for many applications relative energies are the important quantity, sometimes the cal
culation of atomization energies and heats of formation is desired, as for example in the case of
tting the DFTB repulsive potentials. However, the calculation of atomization energies requires
some additional care.
8
It is given by the total energy of a system E
tot
and the atomic energies E
atom
E
At
= E
tot
+
a
E
atom
a
(13)
With a closedshell treatment DFTB gives E
atom
a
of rather poor quality. One may use the spin
polarization formalism, which improves the results. In practice, however, the atomization energies
are usually calculated using spinpolarization energies E
spin
that are precalculated from DFT for
each atom; i.e., E
spin
is the difference of the atomic energy calculated at the spinunpolarized state
and the spinpolarized state.
7
With that, E
atom
is calculated as the total energy of an atom plus the
spinpolarization energy E
spin
.
Note that using E
spin
gives slightly more accurate results than using atomic energies as calcu
lated from spinpolarized DFTB because the spinpolarization from the atom (as calculated from
DFT) is added rather than a correction of the atomic energy. The latter uses spinpolarization con
stants calculated as derivative of the atomic eigenvalues in the proximity of the spinunpolarized
atom.
7
In the case of Hydrogen the spinunpolarized state would refer to a hypothetical one where 0.5 electrons are spin
up and 0.5 electrons are spindown, while the spinpolarized state is the ground state of the atom with 1.0 spinup and
0.0 spindown electrons.
14
Performance
Energetics, structure and vibrational frequencies of small molecules
DFTB2 has been tested over the years for a variety of molecular properties. A rst thorough test
has been performed by Krger et al,
47
who benchmarked the accuracy of DFTB2 against G2 and
BLYP for 22 molecules, evaluating 28 reaction energies, geometries and vibrational frequencies.
Reaction energies show an mean error of 4.3 kcal/mol with respect to G2 and geometries are in
excellent agreement with those obtained at the DFT level. Vibrational frequencies, however, show
larger deviations; in particular, the stretch frequencies of several specic modes are signicantly
overestimated. Therefore, Maolepsza et al.
48
suggested to apply a specic parametrization of
E
rep
for vibrational frequencies. With this special parameter set, DFTB2 shows a very good per
formance and vibrational frequencies approach the quality of those from full DFT. We investigated
this point in more detail in later publications for DFTB2
12
and DFTB3.
8
These studies demon
strate the limited exibility of the current DFTB approach; i.e, it is not possible to achieve an
accuracy comparable to DFTGGA for both reaction energies and vibrational frequencies with a
single parameterization. There is an optimization conict where one property deteriorates when
the other is improved. The pragmatic solution to this problem is to supply two sets of parame
ters,
8
one optimized for energies and geometries (3OB), the other for geometries and vibrational
frequencies (3OBf).
Two other publications have benchmarked DFTB2 for even larger molecular test sets. Sat
telmeyer et al.
49
benchmarked DFTB2 for 622 closed shell molecules containing O, N, C and H in
comparison with HartreeFock based semiempirical methods like AM1, PM3 and PDDG/PM3.
The good performance of DFTB for geometries was conrmed, however, the performance of
DFTB2 for heats of formation with a mean average error of 5.8 kcal/mol was worse than that
of PM3 and PDDG/PM3, the latter with a mean absolute error of 3.2 kcal/mol that even outper
forms B3LYP/631G(d).
8
Otte et al.
50
conrmed these ndings, showing that DFTB2 performs
8
This study also indicated errors in the treatment of NO and SO bonds, which should be ameliorated with the
new 3OB parametrization.
15
slightly worse for heats of formation than AM1 and PM3, and in particular worse than the OMx
suite of methods. However, geometries are very well described and DFTB2 is clearly superior for
vibrational frequencies. Further, DFTB2 performs very well for structures and relative energies of
peptide conformations,
9
as well as for hydrogen bonded systems.
The 3OB parametrization for DFTB3 has been developed with improving two particular lim
itations of DFTB2 in mind: the overbinding of about 510 kcal/mol per covalent bond (for O,
N, C, H containing molecules) and the underestimation of binding energies in weakly bonded
complexes.
8
The thirdorder terms improve the description of localized charges
10
and the modi
ed Coulomb interaction
h
(U
a
, R
ab
) improves hydrogen bonding interactions.
7
As a result, the
description of energies is greatly improved: DFTB3/3OB approaches the accuracy of DFTGGA
methods like PBE for heats of formations and atomization energies as well as the accuracy of the
@@best semiempirical methods like PDDGPM3. DFTB3/3OB is even better than DFTGGA
when only a small, double zeta type basis set is applied,
8
as typically done with DFT or DFT/MM
based molecular dynamics simulations. In particular hydrogen bonding energies, proton afni
ties and proton transfer barriers, which are relevant in many biochemical problems, are very well
described.
Recently, Goerigk and Grimme have compiled a general database (GMTKN24) for main group
thermochemistry, kinetics and noncovalent interactions.
29
This set benchmarks a variety of molec
ular properties, reaction and atomization energies, reaction barriers, electron afnities, ionization
potentials (IPs) and proton afnities (EAs), hydrogen bonding and VdW interactions, conforma
tional energies of peptides, hydrocarbons and carbohydrates, isomerization reactions and some
other properties. For this set, the accuracy of DFTB3/3OB is comparable to the newest variant of
the OMx models,
8
OM3, which has been shown recently to approach the accuracy of DFTGGA
methods for this data set.
53
9
See also Refs. 51,52 for more detail.
10
As they appear in small charged molecules, where the charge is located on few atoms. Large ionic molecules,
where the charge is distributed over a large number of atoms is unproblematic in DFTB2.
16
Properties: IPs, EAs, dipole moments and molecular polarizability
IPs and EAs for small molecules are difcult to compute with a minimal basis set method like
DFTB since these properties do not enter the parametrization procedure, in contrast to NDDO
type semiempirical methods. The adjustment of E
rep
only affects bond lengths (not angles!),
bond energies and stretch frequencies. Therefore, properties like IP and EA are usually less accu
rately described
8,49,50,53
and deserve careful testing for the specic problem in hand. This holds
as well for dipole moments, which are simply computed from the Mulliken population analysis.
The description of electrostatic properties such as dipole moments can be easily improved using a
parametrized charge scheme like CM3, as has been shown in Ref. 17. However, IR intensities are
not changed since these depend on the derivative of the dipole moment with respect to the normal
coordinates, which is not improved. Unfortunately, this holds similarly for molelcular polariz
abilities and Raman intensities. The polarizabilities can be adequately improved using methods
like Chemical Potential equilization
16
or a variational approach (VAR),
17
but Raman intensities
suffer from the same problem as IR intensities; i.e., although the properties are improved, their
derivatives with respect to normal coordinates are not.
Conformations of complex molecules
Most of the tests described so far benchmark the DFTB performance for covalent bond lengths
and bond angles. The performance for dihedral angles, which is important to the description of
conformations of complex molecules like peptides, proteins, DNA and carbohydrates, remains
systematically tested. DFTB2 has been extensively benchmarked for the structures and relative en
ergies of polyalanine conformations.
51,52
Relative energies and structures were found to be in good
agreement with DFT and ab initio predictions, and vibrational spectroscopic features were also re
produced satisfactorily;
54
for a short review, see Ref. 55. However, low frequency modes seem
to be underestimated,
56
which indicates that rotational barriers are too low in DFTB. QM/MM
simulations of dialanine in water indicated that the free energy minima at the helical and 
sheet region were more extended than in standard force eld methods,
57
a nding conrmed later
17
using a different QM/MM implementation.
58
A deeper analysis indeed showed that the rotational
barriers around the dihedral angles are very low. Furthermore, DFTB/MM populates the basin
more than the basin, in contrast to experimental ndings. The energy differences, however, are
small and on the order of 0.5 kcal/mol. Therefore, small changes in the Hamiltonian can lead to
a signicant change in the populations, and it is possible that DFTB3 with an improved QM/MM
coupling (KOscheme, see above) leads to an improvement.
DFTB2 has also been tested for carbohydrates and the property of interest are again the dihe
dral angles, in particular the ring puckering modes. It has been shown that DFTB2 produces free
energy surfaces for conformational transitions similar to those of ab initio methods, in contrast to
various NDDO methods,
59
motivating the application of DFTB2 to carbohydrate reaction dynam
ics.
60,61
The agreement with high level methods, however, is far from perfect and leaves ample
room for future improvement. For example, potential energy scans for certain dihedral angles
clearly showed that DFTB2 is in qualitative agreement with full DFT but with too low torsional
barriers, while NDDO type methods seem to fail even qualitatively.
62
Nevertheless, there seems
no compelling reason to use DFTB2 for the description of structure and dynamics of carbohydrates
at the moment, since empirical force elds currently represent the potential energy surface much
more accurately.
Water
Another issue worth mentioning is the description of water by DFTB. Given its fundamental
importance in chemistry and biology, its desirable to be able to adequately describe water in
both gas and condensed phases, including water in different protonation states (e.g., a solvated
proton/hydroxide). With the standard DFTB2, the hydrogen bonding interaction between water
molecules is too weak; as discussed above and in detail elsewhere,
4,5,7
this motivated the de
velopment of the modied
h
function for atom pairs involving H. With DFTB3
7
and the latest
parameterization,
8
for example, the water dimer binding energy is well described and lowenergy
conformers of small water clusters are also captured. The relative energies of these lowenergy con
18
formers, however, are not yet ideal, suggesting the need of further improving hydrogenbonding
interactions by, for example, going beyond the monopole approximation for chargecharge inter
actions in eq. 8. The imperfection of waterwater interaction is also manifested in bulk water
simulations, which indicated that both DFTB2 and DFTB3 tend to overpredict the height of the
rst solvation shell peak in the OO radial distribution function while underestimating the second
solvation shell.
6365
For NVT simulations at the ambient condition, one simple but ad hoc approach to improve the
description of bulk water is to adjust the pairwise repulsive potentials based on a reversed Monte
Carlo protocol such that experimental radial distribution functions are reproduced. This is found
66
to be somewhat successful in that the resulting repulsive potentials also improved the description
of small protonated water clusters and the structure of a solvated proton. For the 13 lowenergy
isomers H(H
2
O)
+
22
, for example, the RMSE is only 0.9 kcal/mol relative to MP2 results,
67
as
compared to the value of 3.8 kcal/mol for the original DFTB3. For a solvated proton in the bulk,
the integrated coordination number for the rst solvation shell is 3.2, which is close to the value
of 3.0 for CPMD (using the HCTH functional); by comparison, the standard DFTB3 gives a value
close to 5.0.
65
Nevertheless, the enthalpy of evaporation remains too low by about 1 kcal/mol,
and preliminary NPT simulations indicate that DFTB2/3 tends to substantially overestimate the
density of bulk water at the ambient condition, a situation also observed in some ab initio DFT
simulations.
68
Therefore, improving the description of water remains an important topic for further
DFTB developments.
Conclusions
The extension of DFTB to the thirdorder, DFTB3,
7,8
in combination with a new parametrization
procedure
12
has improved the performance signicantly for reaction energies, geometeries and
hydrogen bonded complexes. DFTB3 even outperforms DFTGGA with double zeta (DZ) basis
in special cases, although being 23 orders of magnitude faster.
69
However, the computational
19
efciency comes at the price of reduced transferability; i.e., not all molecular properties can be
computed at the same accuracy within one parameter set. Such an optimization conict has been
found in case of reaction energies and vibrational frequencies, therefore we have proposed to use
two different parametrizations, the 3OB for energies and geometries and 3OBf for geometries and
vibrational frequencies;
8
geometries are described with similar accuracy in both parameter sets.
A key to better nonbonded interactions is the use of the thirdorder term in combination with
the modied Coulomb interaction term,
h
. The augmentation of the DFTB3 total energy with
the empirical dispersion extension can be advised as a default, because it usually only improves
results.
Despite all these improvements, there are still several limitations of DFTB:
(i) The DFTGGA framework used for the expansion of the total energy. The DFTB models
inherit the wellknown DFTGGA problems, especially the selfinteraction error.
(ii) The use of a minimal basis set. This leads to a reduced molecular polarizability and limits
the application of DFTB for computing IR and Raman spectra. Further, the missing polarization
functions may cause problems in the description of sp
3
nitrogen.
8
This shows up in large errors
for proton afnities with acidic nitrogen, for which no satisfactory solution has been proposed up
to now; an ad hoc x is used by applying a special parameter set (NHmod) for these special cases.
(iii) The limited exibility of the scheme (xed initial density, monopole approximation) leaves
further problems. This shows up in the description of atomization energies of ionic species,
8
an
other complication is the need for two different parameter sets for hydrogen. Aspecial parametriza
tion is needed, when the bond breaking of molecular hydrogen is computed.
8
(iv) DFTB describes the general conformational properties of biomolecules quite well: pep
tides, DNA bases and sugars can be computed with often good accuracy. However, DFTB under
estimates torsional barriers, which currently limits its applicability in the description of conforma
tional dynamics of these complex molecules.
Another important direction for DFTB development concerns the treatment of metal ions, such
as Mg
2+
, Zn
2+
and Cu
+/2+
, which play important structural and catalytic roles in biomolecules.
20
DFTB2 has been parameterized for several rstrow elements (e.g., Fe, Ni, Co, Cu and Zn),
7072
and it has been shown that DFTB2 generally gives reliable structural properties for metal sites,
including fairly complex bimetallo zinc sites,
7378
and DFTB/MM has been successfully applied
to a number of metalloenzymes by us and other research groups.
7379
Pushing forward the DFTB
framework is signicant for metalloenzyme applications because for transition metal ions, despite
progress,
80,81
a robust semiempirical method (even just for structures!) is not yet available. This
is particularly true for openshell cases: although parameterizations for several openshell metal
ions (e.g., Ni, Cu and Fe) have been reported in the literature,
71,72,82
their application has largely
been limited to geometry optimization of organometallic compounds and only several metalloen
zymes;
83
systematic development of the methodology to improve energetics remains an important
frontier.
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