Journal of Chemistry

Volume 2013 (2013), Article ID 803151, 6 pages

http://dx.doi.org/10.1155/2013/803151

Research Article

ITP Adjuster 1.0: A New Utility Program to Adjust Charges in the Topology Files Generated by the PRODRG Server

Diogo de Jesus Medeiros,¹ Wilian Augusto Cortopassi,1,2 Tanos Celmar Costa França,² and André Silva Pimentel¹

¹Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rua Marquês de São Vicente 225, Gávea, 22453-900 Rio de Janeiro, RJ, Brazil

²Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense (LMCBD), Military Institute of Engineering, Praça General Tibúrcio, 80, Urca, 22290-270 Rio de Janeiro, RJ, Brazil

Received 30 June 2012; Accepted 3 August 2012

Academic Editor: Cristiano R. W. Guimarães

Copyright © 2013 Diogo de Jesus Medeiros et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

The suitable computation of accurate atomic charges for the GROMACS topology *.itp files of small molecules, generated in the PRODRG server, has been a tricky task nowadays because it does not calculate atomic charges using an ab initio method. Usually additional steps of structure optimization and charges calculation, followed by a tedious manual replacement of atomic charges in the *.itp file, are needed. In order to assist this task, we report here the ITP Adjuster 1.0, a utility program developed to perform the replacement of the PRODRG charges in the *.itp files of small molecules by ab initio charges.

1. Introduction

The GROMACS package [1] is extensively used for energy minimizations (EM) and molecular dynamics (MD) simulations of biomolecules such as proteins, nucleic acids, peptides, and drugs [2–11]. The input topology files used by GROMACS [1] for small molecules (*.itp files) may be generated by the server PRODRG [12]. However, these files must be adjusted for MD due to the charge group concepts adopted by PRODRG [12].

The topology files preparation for performing EM and MD simulations with GROMACS [1] is very important in investigations of biological processes involving drug interactions with their molecular targets. The force fields available for biomolecules in the literature [13–16] are generally based on macromolecules, such as proteins and nucleic acids, making the preparation of consistent and reliable topology files for small ordinary molecules a challenging task. The PRODRG server [12] is a reliable tool for quickly generating topologies and coordinates of ligands in protein-ligand complexes, using the empirical GROMOS96 force field [14], from a variety of different input files. This tool has been used in several studies and a wide range of knowledge areas [17–25]. This server works with the concept of charge groups, which is defined as a group of bonded atoms that sums an integer total charge. Lemkul et al. [26] investigated the quality of topologies generated by the PRODRG server [12] for small molecules for the GROMOS96 43A1 force field [14] and described their functional groups. Their results show that the atomic partial charges are critically incompatible with the GROMOS force fields. Furthermore, when we use the PRODRG [12] parameters, the behavior of the system is notably different than the one observed using the GROMOS parameters. Thus, they suggest a more consistent strategy for the calculation of partial atomic charges, avoiding the deviation of behavior in the system.

Several computer programs are available for structure optimization and charge calculations using quantum chemical calculations [27–29]. The Frisch et al. software [30] has been reported as the most standard for quantum chemical calculations of small molecules [31–33]. Thus, the ITP adjuster 1.0 was built to make the interface of Frisch et al. [30] with the GROMACS package [1]. However, it may also be easily modified to work with different quantum chemical softwares.

There are several problems to adjust the output files of PRODRG [12] based on Frisch et al. [30] output files (*.out files): (i) the manual edition of the topology charges is an exhausting, tedious, and time-demanding assignment and, so, very susceptible to mistakes; (ii) PRODRG [12] uses a charge group concept, differently from Frisch et al. [30] and any other quantum chemical softwares; (iii) the numbering of hydrogen atoms in the *.itp files is incompatible with the output files from quantum chemical softwares; (iv) the bonds information in the Frisch et al. [30] output files may have some inconsistencies, such as hydrogen atoms bonded to two different atoms.

The ITP Adjuster 1.0 (Figure 1) performs a quick and safe edition of the *.itp files considering the charge calculations from Frisch et al. [30] using Mulliken or Chelpg (Charges from Electrostatic Potentials) charges. It handles charges of up to six decimal places. At the end of the execution, a message box will inform the total charge of the molecule in the edited *.itp file, which may be used as a guide to detect inconsistencies between the *.itp and *.out files.

Figure 1: The ITP Adjuster interface.

2. Materials and Methods

2.1. Considerations for Using ITP Adjuster

Some requirements for using the ITP Adjuster 1.0 are important to guarantee its proper installation and use, as discussed below.

ITP Adjuster 1.0 needs the Microsoft.Net Framework 4 or later installed for running properly. The authors recommend the Frisch et al. [30] calculations and PRODRG server [12] topology generation. It is highly desirable to have a *.pdb file with numbered atom names before submitting it to the PRODRG server [12]. It guarantees the correspondence of the atom names between the *.out and the final *.itp files. ITP Adjuster 1.0 also has a functionality named “PDB Adjustment,” which verifies a *.pdb file and, if necessary, numbers the atom names.

The hydrogen charges are based on the information of bonds presented in the Frisch et al. [30] output files, which is necessary to provide an *.itp file which is compatible with the *.out file indicated. An usual mistake occurs when the PRODRG server [12] removes hydrogen atoms from oxygen and nitrogen atoms or adds hydrogen atoms that do not exist in the *.out file. In these cases, the user must use the ADDHYD, DELHYD, PATCH, or a combination of these commands in the PRODRG server [12] in order to correct these inconsistencies before using ITP Adjuster 1.0. Not performing this strategy leads to unreliable final *.itp files and meaningless total charges.

3. Results and Discussion

3.1. Validating ITP Adjuster 1.0

We validated the ITP Adjuster 1.0 with the three common molecules in biological systems: folic acid, adenosine-5′-triphosphate (ATP), and cystein. Structures of these molecules are shown in Figure 2. First we built their 3D structures in the *.pdb format using Gauss View 4.0 and Frisch et al. [30] and submitted them to energy minimization with Frisch et al. [30] using the algorithm B3LYP/3-21G with charge chelpg, in order to generate their *.out files. Besides, the *.itp files of each molecule were generated at the PRODRG server [12]. The *.out and *.itp files were then loaded into the ITP Adjuster 1.0 to change the charges of the *.itp files generated by the PRODRG server [12] by using ab initio charges of the *.out files from Frisch et al. [30]. The results are presented in Tables 1, 2, and 3. As it can be seen, the ITP Adjuster 1.0 was able to recognize the atoms in each file. It properly adjusted the charges without modifying the positions of the atoms. The ITP Adjuster 1.0 was also tested against several other small molecules (data not shown) and, without exception, it was able to adjust charges accordingly.

Table 1: *.itp files of folic acid before (left) and after (right) applying ITP Adjuster 1.0.

Nr
Type
resnr
resid
Atom
cgnr
Charge
Mass
Nr
Type
resnr
resid
Atom
cgnr
Charge
Mass

1
CR1
1
FOL
C15
1
0.022
12.0110
1
CR1
1
FOL
C15
1
0.113688
12.0110

2
HC
1
FOL
H15
1
0.058
1.0080
2
HC
1
FOL
H15
1
0.091572
1.0080

3
NR
1
FOL
N3
1
−0.434
14.0067
3
NR
1
FOL
N3
1
−0.504841
14.0067

4
C
1
FOL
C16
1
0.335
12.0110
4
C
1
FOL
C16
1
0.798970
12.0110

5
NR
1
FOL
N6
1
−0.434
14.0067
5
NR
1
FOL
N6
1
−0.821446
14.0067

6
C
1
FOL
C19
1
0.453
12.0110
6
C
1
FOL
C19
1
0.946175
12.0110

7
NT
1
FOL
N7
2
0.082
14.0067
7
NT
1
FOL
N7
2
−0.931989
14.0067

8
H
1
FOL
H72
2
0.027
1.0080
8
H
1
FOL
H72
2
0.414024
1.0080

9
H
1
FOL
H71
2
0.027
1.0080
9
H
1
FOL
H71
2
0.433222
1.0080

10
NR
1
FOL
N5
2
0.061
14.0067
10
NR
1
FOL
N5
2
−0.786769
14.0067

11
H
1
FOL
H53
2
0.027
1.0080
11
H
1
FOL
H53
2
0.414871
1.0080

12
C
1
FOL
C18
2
0.294
12.0110
12
C
1
FOL
C18
2
0.698881
12.0110

13
O
1
FOL
O4
2
−0.676
15.9994
13
O
1
FOL
O4
2
−0.485705
15.9994

14
C
1
FOL
C17
2
0.158
12.0110
14
C
1
FOL
C17
2
−0.275218
12.0110

15
NR
1
FOL
N4
3
−0.619
14.0067
15
NR
1
FOL
N4
3
−0.194434
14.0067

16
C
1
FOL
C14
3
0.127
12.0110
16
C
1
FOL
C14
3
0.172175
12.0110

17
CH2
1
FOL
C13
3
0.161
14.0270
17
CH2
1
FOL
C13
3
0.134163
14.0270

18
N
1
FOL
N2
3
0.127
14.0067
18
N
1
FOL
N2
3
−0.476189
14.0067

19
H
1
FOL
H22
3
0.021
1.0080
19
H
1
FOL
H22
3
0.222443
1.0080

20
C
1
FOL
C3
3
0.127
12.0110
20
C
1
FOL
C3
3
0.404365
12.0110

21
CR1
1
FOL
C4
3
0.015
12.0110
21
CR1
1
FOL
C4
3
−0.305799
12.0110

22
HC
1
FOL
H4
3
0.041
1.0080
22
HC
1
FOL
H4
3
0.156776
1.0080

23
CR1
1
FOL
C5
4
0.000
12.0110
23
CR1
1
FOL
C5
4
−0.091238
12.0110

24
HC
1
FOL
H51
4
0.000
1.0080
24
HC
1
FOL
H51
4
0.118576
1.0080

25
CR1
1
FOL
C2
4
0.000
12.0110
25
CR1
1
FOL
C2
4
−0.334445
12.0110

26
HC
1
FOL
H21
4
0.000
1.0080
26
HC
1
FOL
H21
4
0.172869
1.0080

27
CR1
1
FOL
C1
4
0.000
12.0110
27
CR1
1
FOL
C1
4
−0.022017
12.0110

28
HC
1
FOL
H11
4
0.000
1.0080
28
HC
1
FOL
H11
4
0.106113
1.0080

29
C
1
FOL
C6
4
0.000
12.0110
29
C
1
FOL
C6
4
−0.147662
12.0110

30
C
1
FOL
C7
5
0.429
12.0110
30
C
1
FOL
C7
5
0.566722
12.0110

31
O
1
FOL
O1
5
−0.612
15.9994
31
O
1
FOL
O1
5
−0.487695
15.9994

32
N
1
FOL
N1
5
0.176
14.0067
32
N
1
FOL
N1
5
−0.654534
14.0067

33
H
1
FOL
H12
5
0.030
1.0080
33
H
1
FOL
H12
5
0.322800
1.0080

34
CH1
1
FOL
C8
5
0.229
13.0190
34
CH1
1
FOL
C8
5
0.290274
13.0190

35
C
1
FOL
C12
5
0.428
12.0110
35
C
1
FOL
C12
5
0.640657
12.0110

36
O
1
FOL
O3
5
−0.612
15.9994
36
O
1
FOL
O3
5
−0.499644
15.9994

37
OA
1
FOL
O6
5
−0.149
15.9994
37
OA
1
FOL
O6
5
−0.637158
15.9994

38
H
1
FOL
H6
5
0.081
1.0080
38
H
1
FOL
H6
5
0.456952
1.0080

39
CH2
1
FOL
C9
6
0.198
14.0270
39
CH2
1
FOL
C9
6
0.004713
14.0270

40
CH2
1
FOL
C10
6
0.198
14.0270
40
CH2
1
FOL
C10
6
−0.014129
14.0270

41
C
1
FOL
C11
6
0.384
12.0110
41
C
1
FOL
C11
6
0.703747
12.0110

42
O
1
FOL
O2
6
−0.685
15.9994
42
O
1
FOL
O2
6
−0.512801
15.9994

43
OA
1
FOL
O5
6
−0.167
15.9994
43
OA
1
FOL
O5
6
−0.633904
15.9994

44
H
1
FOL
H52
6
0.072
1.0080
44
H
1
FOL
H52
6
0.432867
1.0080

Table 2: *.itp files of cystein before (left) and after (right) applying ITP Adjuster 1.0.

Nr
Type
resnr
resid
Atom
cgnr
Charge
Mass
Nr
Type
resnr
resid
Atom
cgnr
Charge
Mass

1
OA
1
CYS
O2
1
−0.180
15.9994
1
OA
1
CYS
O2
1
−0.553855
15.9994

2
H
1
CYS
H22
1
0.057
1.0080
2
H
1
CYS
H22
1
0.366426
1.0080

3
C
1
CYS
C3
1
0.372
12.0110
3
C
1
CYS
C3
1
0.638891
12.0110

4
O
1
CYS
O1
1
−0.693
15.9994
4
O
1
CYS
O1
1
−0.478926
15.9994

5
CH1
1
CYS
C2
1
0.175
13.0190
5
CH1
1
CYS
C2
1
0.098300
13.0190

6
NT
1
CYS
N1
1
0.066
14.0067
6
NT
1
CYS
N1
1
−0.630975
14.0067

7
H
1
CYS
H16
1
0.012
1.0080
7
H
1
CYS
H16
1
0.282228
1.0080

8
H
1
CYS
H15
1
0.012
1.0080
8
H
1
CYS
H15
1
0.282036
1.0080

9
CH2
1
CYS
C1
1
0.153
14.0270
9
CH2
1
CYS
C1
1
−0.101843
14.0270

10
S
1
CYS
S1
1
0.077
32.0600
10
S
1
CYS
S1
1
0.049643
32.0600

11
H
1
CYS
H13
1
−0.051
1.0080
11
H
1
CYS
H13
1
0.048076
1.0080

Table 3: *.itp files of ATP before (left) and after (right) applying ITP Adjuster 1.0.

Nr
Type
resnr
resid
Atom
cgnr
Charge
Mass
Nr
Type
resnr
resid
Atom
cgnr
Charge
Mass

1
OA
1
ATP
012
1
−0.256
15.9994
1
OA
1
ATP
012
1
−0.674862
15.9994

2
H
1
ATP
H12
1
0.001
1.0080
2
H
1
ATP
H12
1
0.395648
1.0080

3
P
1
ATP
P3
1
1.081
30.9738
3
P
1
ATP
P3
1
1.542343
30.9738

4
OA
1
ATP
O13
1
−0.256
15.9994
4
OA
1
ATP
O13
1
−0.731008
15.9994

5
H
1
ATP
H13
1
0.001
1.0080
5
H
1
ATP
H13
1
0.418396
1.0080

6
OM
1
ATP
O7
1
−0.151
15.9994
6
OM
1
ATP
O7
1
−0.606703
15.9994

7
OA
1
ATP
O6
1
0.246
15.9994
7
OA
1
ATP
O6
1
−0.781970
15.9994

8
P
1
ATP
P2
1
1.081
30.9738
8
P
1
ATP
P2
1
1.666306
30.9738

9
OA
1
ATP
O11
1
−0.256
15.9994
9
OA
1
ATP
O11
1
−0.709606
15.9994

10
H
1
ATP
H11
1
0.001
1.0080
10
H
1
ATP
H11
1
0.430751
1.0080

11
OM
1
ATP
O5
2
0.000
15.9994
11
OM
1
ATP
O5
2
−0.656411
15.9994

12
OA
1
ATP
O4
3
−0.191
15.9994
12
OA
1
ATP
O4
3
−0.836197
15.9994

13
P
1
ATP
P1
3
1.389
30.9738
13
P
1
ATP
P1
3
1.661303
30.9738

14
OA
1
ATP
O10
3
−0.199
15.9994
14
OA
1
ATP
O10
3
−0.668092
15.9994

15
H
1
ATP
H93
3
0.001
1.0080
15
H
1
ATP
H93
3
0.410779
1.0080

16
OM
1
ATP
O3
4
−0.177
15.9994
16
OM
1
ATP
O3
4
−0.641581
15.9994

17
OA
1
ATP
O2
4
−0.289
15.9994
17
OA
1
ATP
O2
4
−0.604805
15.9994

18
CH2
1
ATP
C10
4
−0.062
12.0110
18
CH2
1
ATP
C10
4
0.301881
12.0110

19
CH1
1
ATP
C9
4
0.093
12.0110
19
CH1
1
ATP
C9
4
0.289979
12.0110

20
OA
1
ATP
O1
4
−0.289
15.9994
20
OA
1
ATP
O1
4
−0.515384
15.9994

21
CH1
1
ATP
C8
4
0.024
12.0110
21
CH1
1
ATP
C8
4
0.189925
12.0110

22
OA
1
ATP
O8
4
−0.301
15.9994
22
OA
1
ATP
O8
4
−0.558061
15.9994

23
H
1
ATP
H82
4
0.001
1.0080
23
H
1
ATP
H82
4
0.358163
1.0080

24
CH1
1
ATP
C7
5
0.047
12.0110
24
CH1
1
ATP
C7
5
0.186587
12.0110

25
OA
1
ATP
O9
5
0.261
15.9994
25
OA
1
ATP
O9
5
−0.541491
15.9994

26
H
1
ATP
H92
5
0.001
1.0080
26
H
1
ATP
H92
5
0.370706
1.0080

27
CH1
1
ATP
C6
5
0.126
12.0110
27
CH1
1
ATP
C6
5
0.578117
12.0110

28
NR
1
ATP
N3
5
0.169
14.0067
28
NR
1
ATP
N3
5
−0.804205
14.0067

29
CR1
1
ATP
C5
5
−0.059
12.0110
29
CR1
1
ATP
C5
5
0.257766
12.0110

30
HC
1
ATP
H51
5
−0.023
1.0080
30
HC
1
ATP
H51
5
0.276650
1.0080

31
NR
1
ATP
N4
6
−0.499
14.0067
31
NR
1
ATP
N4
6
−0.572949
14.0067

32
C
1
ATP
C3
6
0.096
12.0110
32
C
1
ATP
C3
6
0.176370
12.0110

33
C
1
ATP
C4
6
0.247
12.0110
33
C
1
ATP
C4
6
0.666733
12.0110

34
NR
1
ATP
N2
6
−0.512
14.0067
34
NR
1
ATP
N2
6
−0.611459
14.0067

35
CR1
1
ATP
C1
6
−0.048
12.0110
35
CR1
1
ATP
C1
6
0.210905
12.0110

36
HC
1
ATP
H1
6
−0.019
1.0080
36
HC
1
ATP
H1
6
0.220957
1.0080

37
NR
1
ATP
N1
6
−0.512
14.0067
37
NR
1
ATP
N1
6
−0.605878
14.0067

38
C
1
ATP
C2
6
0.247
12.0110
38
C
1
ATP
C2
6
0.640460
12.0110

39
NT
1
ATP
N5
7
0.031
14.0270
39
NT
1
ATP
N5
7
−0.794455
14.0270

40
H
1
ATP
H53
7
−0.016
1.0080
40
H
1
ATP
H53
7
0.327604
1.0080

41
H
1
ATP
H52
7
−0.015
1.0080
41
H
1
ATP
H52
7
0.336786
1.0080

Figure 2: Structures of some molecules tested with ATP adjuster 1.0.

4. Conclusion

We reported here the development of the ITP Adjuster 1.0, a utility program built to adjust ab initio charges into *.itp files generated by the PRODRG server [12]. This utility program is already in use in our laboratory and proved to be very accurate in the interface of Frisch et al. [30] and GROMACS [1], providing a friendly user interface and a quick way to generate suitable topology files to perform EM and MD calculations with the GROMACS package [1].

This utility program is available free of charge by request at lmm@puc-rio.br.

Conflict of Interests

All the authors declare that there is no conflict of interests related to the publishing of this paper on the Journal of Chemistry or any direct financial relation with the trademarks mentioned in the paper.

Acknowledgments

The authors thank the Brazilian funding agencies CNPq (Grant no. 304187/2009-7), CAPES (Grant no. 02559/09-9), and FAPERJ (Grant nos. E-26/101.452/2010 and E-26-111.532/2008) for financial support. W. A. Cortopassi also thanks CNPq, FAPERJ, the Estudar Foundation, and DMBranco for financial support and fellowship. A. S. Pimentel and T. C. C. Franca are recipients of the FAPERJ Young Scientist of Our State award.

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