Titprot

Titprot is a simple Monte Carlo program to titrate proteins and changed the conformation of residues, as well as rotate hydrogen atoms.
It uses an atomistic model of the protein, with atomic charges, but the protein is fixed in space; only counter ions are moving.
It uses a primitive model (i.e. hard spheres with an radius of 2.0 Å for each atom) and electrostatic interactions are calculated with Coulomb's law, using a dielectric constant of 80.

Currently implemented are

Titration of Asp, Glu, Lys, Arg, Tyr, and Cys
Titration of amino and carboxy terminals (specified by residue numbers)
Titration of ionic pairs (specified by amino-acid numbers)
Conformations of Ash, Glh, and carboxy terminals (two different O atoms and two H positions, syn or anti), i.e. totally four conformations
Conformations of Tyr (two positions of the HO)
Conformations of His (Hid or Hie, but also rotation of the His ring 180 deg)
Conformations of Asn and Gln (botation of the side chain 180 deg
Rotation of Ser, Thr, Lys, Lyn, and Tyr (and all methyl groups also, if needed)
Rotation of water molecules (first atom anywhere on a sphere, second on a circle)

The program may write out restart files as well as coordinate snap-shot files with extra atoms deleted.

The program is not yet published.

The files are in /away/bio/Titrprot
The executables are in /away/bio/Bin/Linux/titprot

Start a calculation

Start with a pdb file.
Protonate it, e.g. with tleap + changeparm.
Add additional protons and construct the excluded-atom lists (both 1-2/1-3 and 1-4) with changepdb, command ti.
For a full calculation, you should answer 4 to OXT and yes to all other questions.
Note that the program will not recognize GLH or ASH - they should be avoided.
Construct the titprot.dat input file. See the template below.
If you want to titrate the amino and carboxy terminals, these have to be set up by hand (see the template below). Insert the residue numbers and replace the charges of the first state with the charges from the original pdb file. The charges from the neutral site are taken from LYN and GLH, respectively. The charge on CA will have to be adapted to get a correct total charge.

Ionic pairs can be found by changepdb, command bc.
Insert this list and remove duplicates.
Run the program
titprot >output

If the program crashes with the message:
Incorrect atom names or charges in residue
It probably means that you have non-standard charges of that residue. This is not allowed for a titrating residue.

Note that the program is quite new and not very well tested. There may still be unrecovered bugs. However, it gives a reasonable titration profile for test proteins.

With 2300 protein atoms and 185 ions in a 83.3 Å sphere, 10M MC steps took less than 3 h on milleotto. With 5M equilibration steps (probably too much), average charge is converged to within 0.02 e, average rotations to within 2 deg, and conformation states to within 2%, but total energy is not better than within 10%.

To get the right concentration of the protein:
$box size = 14.72/(conc_prot^(1/3)) Å
To get the right numer of ions (given a concentration):
$nion = 0.0003123 * conc_ion * $box_size^3

Valid commands in the titprot.dat file

Each command start with $ and a keyword on a line.
All data are read in free format

$title       - title of the calculation (any number of lines)
$ph          - the pH value
$iontypes    - number of different types of ions (typically 2)
$nions       - number of ions of each type
$ion charge - charge of ions of each type
$ion radii   - raddi of ions of each type
$temperature - temperature in K
$iterations - number of Monte Carlo steps
$equilibrate - number of steps to skip before averages are collected (default = half)
$box size    - diameter of the simulated sphere in Å (166.6 gives a protein conc of 0.7 mM)
$titmod      - number of ion moves between each titration attempt
$confmod     - number of ion moves between each attempt to change conformation
$rotmod    - number of ion moves between each attempt to rotate a bond
$pdb file    - name of the input pdb file (with charges)
$excluded    - name of the file with the excluded atom lists
$conformation description of the conformations to change (see below)
                  number of residues for which the conformation will be changed
                  name of the residue for which the conformation will be changed
                  number of atoms that will move in the conformation
                  name of the residue in each conformation
                  name and charge of each atom for each conformation
$rotate      - description of the rotations to change (see below)
                  number of rotations
                  residue to rotate
                  number of atoms to rotate
                  name of atoms to rotate
                  name of atoms that form a bond, angle, and dihedral
$rot water   - rotate all water molecules
$titrate     - description of the residues to titrate (see below)
                   number of different residues
                   name of residue (or residue followed by residue number)
                   number of atoms, number of conformations, ideal pKa
                   name of each conformation
                   atom name and charge for each atom and conformation
$write coord   - number of step between which coordinates are sampled
$write restart - number of step between which a restart file is written (iterations/10)
$restart       - the input file is a restart file
$random seed   - seed for the random number generator
$end           - end of input after which no data is read
#comment       - Every line starting with # is ignored

Template titprot.dat file

Note that the protein charges come from Amber 1994/99 force field.

$title
Calmodulin + real peptide charge=7
$ph
7
$iontypes
2
$nions
101 84
$ion charge
1 -1
$ion radii
2.   2.
$temperature
300
$iterations
10000000
$equilibrate
5000000
$box size
166.6
$titmod
10
$confmod
10
$pdb file
u
$excluded
exclude
$conformation
2
GLN
6 2
GLN
OE1 -0.6086 NE2 -0.9407
HE11 0.0000 HE21 0.4251
HE12 0.0000 HE22 0.4251
NE2 -0.9407 OE1 -0.6086
HE21 0.4251 HE11 0.0000
HE22 0.4251 HE12 0.0000
ASN
6 2
ASN
OD1 -0.5931 ND2 -0.9191
HD11 0.0000 HD21 0.4196
HD12 0.0000 HD22 0.4196
ND2 -0.9191 OD1 -0.5931
HD21 0.4196 HD11 0.0000
HD22 0.4196 HD12 0.0000
$rotate
6
SER
1
HG
OG CB CA
THR
1
HG1
OG1 CB CA
CYS CYM
1
HG
SG CB CA
TYR TYM
1
HH
OH CZ CE1
LYS=LYN
3
HZ1 HZ2 HZ3
NZ CE CD
TAT=TAN
3
H1 H2 H3
N   CA C
$rot water
$rotmod
10
$titrate
9
GLU
19 5 4.4
GLH GLH GLH GLH
N      -0.5163 N     -0.4157 N     -0.4157 N     -0.4157 N     -0.4157
H       0.2936 H      0.2719 H      0.2719 H      0.2719 H      0.2719
CA      0.0397 CA     0.0145 CA     0.0145 CA     0.0145 CA     0.0145
HA      0.1105 HA     0.0779 HA     0.0779 HA     0.0779 HA     0.0779
CB      0.0560 CB    -0.0071 CB    -0.0071 CB    -0.0071 CB    -0.0071
HB2    -0.0173 HB2    0.0256 HB2    0.0256 HB2    0.0256 HB2    0.0256
HB3    -0.0173 HB3    0.0256 HB3    0.0256 HB3    0.0256 HB3    0.0256
CG      0.0136 CG    -0.0174 CG    -0.0174 CG    -0.0174 CG    -0.0174
HG2    -0.0425 HG2    0.0430 HG2    0.0430 HG2    0.0430 HG2    0.0430
HG3    -0.0425 HG3    0.0430 HG3    0.0430 HG3    0.0430 HG3    0.0430
CD      0.8054 CD     0.6801 CD     0.6801 CD     0.6801 CD     0.6801
OE1    -0.8188 OE1   -0.5838 OE1   -0.5838 OE2   -0.6511 OE2   -0.6511
HE11    0.0000 HE11   0.0000 HE11   0.0000 HE2    0.4641 HE22   0.0000
HE12    0.0000 HE12   0.0000 HE12   0.0000 HE22   0.0000 HE2    0.4641
OE2    -0.8188 OE2   -0.6511 OE2   -0.6511 OE1   -0.5838 OE1   -0.5838
HE2     0.0000 HE2    0.4641 HE22   0.0000 HE11   0.0000 HE11   0.0000
HE22    0.0000 HE22   0.0000 HE2    0.4641 HE12   0.0000 HE12   0.0000
C       0.5366 C      0.5973 C      0.5973 C      0.5973 C      0.5973
O      -0.5819 O     -0.5679 O     -0.5679 O     -0.5679 O     -0.5679
ASP
16 5 4.0
ASH ASH ASH ASH
N      -0.5163 N     -0.4157 N     -0.4157 N     -0.4157 N     -0.4157
H       0.2936 H      0.2719 H      0.2719 H      0.2719 H      0.2719
CA      0.0381 CA     0.0341 CA     0.0341 CA     0.0341 CA     0.0341
HA      0.0880 HA     0.0864 HA     0.0864 HA     0.0864 HA     0.0864
CB     -0.0303 CB    -0.0316 CB    -0.0316 CB    -0.0316 CB    -0.0316
HB2    -0.0122 HB2    0.0488 HB2    0.0488 HB2    0.0488 HB2    0.0488
HB3    -0.0122 HB3    0.0488 HB3    0.0488 HB3    0.0488 HB3    0.0488
CG      0.7994 CG     0.6462 CG     0.6462 CG     0.6462 CG     0.6462
OD1    -0.8014 OD1   -0.5554 OD1   -0.5554 OD2   -0.6376 OD2   -0.6376
HD11    0.0000 HD11   0.0000 HD11   0.0000 HD2    0.4747 HD22   0.0000
HD12    0.0000 HD12   0.0000 HD12   0.0000 HD22   0.0000 HD2    0.4747
OD2    -0.8014 OD2   -0.6376 OD2   -0.6376 OD1   -0.5554 OD1   -0.5554
HD2     0.0000 HD2    0.4747 HD22   0.0000 HD11   0.0000 HD11   0.0000
HD22    0.0000 HD22   0.0000 HD2    0.4747 HD12   0.0000 HD12   0.0000
C       0.5366 C      0.5973 C      0.5973 C      0.5973 C      0.5973
O      -0.5819 O     -0.5679 O     -0.5679 O     -0.5679 O     -0.5679
CYM
7 2 9.5
CYS
CA     -0.0351 CA     0.0213
HA      0.0508 HA     0.1124
CB     -0.2413 CB    -0.1231
HB2     0.1122 HB2    0.1112
HB3     0.1122 HB3    0.1112
SG     -0.8844 SG    -0.3119
HG      0.0000 HG     0.1933
HIP
18 6 6.8
HIP HID HID HIE HIE
N      -0.3479 N     -0.3479 N    -0.4157 N    -0.4157 N    -0.4157 N    -0.4157
H       0.2747 H      0.2747 H     0.2719 H     0.2719 H     0.2719 H     0.2719
CA     -0.1354 CA    -0.1354 CA    0.0188 CA    0.0188 CA   -0.0581 CA   -0.0581
HA      0.1212 HA     0.1212 HA    0.0881 HA    0.0881 HA    0.1360 HA    0.1360
CB     -0.0414 CB    -0.0414 CB   -0.0462 CB   -0.0462 CB   -0.0074 CB   -0.0074
HB2     0.0810 HB2    0.0810 HB2   0.0402 HB2   0.0402 HB2   0.0367 HB2   0.0367
HB3     0.0810 HB3    0.0810 HB3   0.0402 HB3   0.0402 HB3   0.0367 HB3   0.0367
CG     -0.0012 CG    -0.0012 CG   -0.0266 CG   -0.0266 CG    0.1868 CG    0.1868
ND1    -0.1513 ND1   -0.1141 ND1 -0.3811 CD2   0.1292 ND1 -0.5432 CD2 -0.2207
HD1     0.3866 HD1    0.2317 HD1   0.3649 HD2   0.1147 HD1   0.0000 HD2   0.1862
CE1    -0.0170 CE1   -0.1718 CE1   0.2057 NE2 -0.5727 CE1   0.1635 NE2 -0.2795
HE1     0.2681 HE1    0.3911 HE1   0.1392 HE2   0.0000 HE1   0.1435 HE2   0.3339
NE2    -0.1718 NE2   -0.0170 NE2 -0.5727 CE1   0.2057 NE2 -0.2795 CE1   0.1635
HE2     0.3911 HE2    0.2681 HE2   0.0000 HE1   0.1392 HE2   0.3339 HE1   0.1435
CD2    -0.1141 CD2   -0.1513 CD2   0.1292 ND1 -0.3811 CD2 -0.2207 ND1 -0.5432
HD2     0.2317 HD2    0.3866 HD2   0.1147 HD1   0.3649 HD2   0.1862 HD1   0.0000
C       0.7341 C      0.7341 C     0.5973 C     0.5973 C     0.5973 C     0.5973
O      -0.5894 O     -0.5894 O    -0.5679 O    -0.5679 O    -0.5679 O    -0.5679
LYS
22 2 10.4
LYN
N      -0.3479 N     -0.4157
H       0.2747 H      0.2719
CA     -0.2400 CA    -0.0720
HA      0.1426 HA     0.0994
CB     -0.0094 CB    -0.0484
HB2     0.0362 HB2    0.0340
HB3     0.0362 HB3    0.0340
CG      0.0187 CG     0.0661
HG2     0.0103 HG2    0.0104
HG3     0.0103 HG3    0.0104
CD     -0.0479 CD    -0.0376
HD2     0.0621 HD2    0.0115
HD3     0.0621 HD3    0.0115
CE     -0.0143 CE     0.3260
HE2     0.1135 HE2   -0.0335
HE3     0.1135 HE3   -0.0335
NZ     -0.3854 NZ    -1.0358
HZ1     0.3400 HZ1    0.3860
HZ2     0.3400 HZ2    0.3860
HZ3     0.3400 HZ3    0.0000
C       0.7341 C      0.5973
O      -0.5894 O     -0.5679
ARG
24 2 12.0
ARN
N      -0.3479 N     -0.6143
H       0.2747 H      0.3753
CA     -0.2637 CA    -0.0484
HA      0.1560 HA     0.0955
CB     -0.0007 CB     0.0233
HB2     0.0327 HB2    0.0330
HB3     0.0327 HB3    0.0330
CG      0.0390 CG     0.1592
HG2     0.0285 HG2   -0.0589
HG3     0.0285 HG3   -0.0589
CD      0.0486 CD     0.2089
HD2     0.0687 HD2    0.0251
HD3     0.0687 HD3    0.0251
NE     -0.5295 NE    -0.8604
HE      0.3456 HE     0.3757
CZ      0.8076 CZ     0.9189
NH1    -0.8627 NH1   -0.9198
HH11    0.4478 HH11   0.3927
HH12    0.4478 HH12   0.3927
NH2    -0.8627 NH2   -0.9428
HH21    0.4478 HH21   0.3592
HH22    0.4478 HH22   0.0000
C       0.7341 C      0.6892
O      -0.5894 O     -0.6033
TYM
21 2 9.6
TYR
N      -0.7563 N     -0.4157
H       0.3510 H      0.2719
CA      0.2310 CA    -0.0014
HA     -0.0073 HA     0.0876
CB     -0.0621 CB    -0.0152
HB2     0.0063 HB2    0.0295
HB3     0.0063 HB3    0.0295
CG     -0.0531 CG    -0.0011
CD1    -0.1424 CD1   -0.1906
HD1     0.1250 HD1    0.1699
CE1    -0.5133 CE1   -0.2341
HE1     0.1425 HE1    0.1656
CZ      0.7722 CZ     0.3226
OH     -0.8068 OH    -0.5579
HH      0.0000 HH     0.3992
CE2    -0.5133 CE2   -0.2341
HE2     0.1425 HE2    0.1656
CD2    -0.1424 CD2   -0.1906
HD2     0.1250 HD2    0.1699
C       0.6972 C      0.5973
O      -0.6020 O     -0.5679
residue 1
5 2 7.5
TAT TAN
CA      0.0034 CA     0.0286
N       0.1812 N     -1.0358
H1      0.1934 H1     0.3860
H2      0.1934 H2     0.3860
H3      0.1934 H3     0.0000
residue 138
8 5 3.8
TCT TCN TCN TCN TCN
CA    -0.2420 CA     0.0209 CA     0.0209 CA     0.0209 CA     0.0209
C      0.7810 C      0.6801 C      0.6801 C      0.6801 C      0.6801
O     -0.8044 O     -0.5838 O     -0.5838 OXT   -0.5838 OXT   -0.5838
HO11   0.0000 HO11   0.0000 HO11   0.0000 HOX    0.4641 HOX2   0.0000
HO12   0.0000 HO12   0.0000 HO12   0.0000 HOX2   0.0000 HOX    0.4641
OXT   -0.8044 OXT   -0.6511 OXT   -0.6511 O     -0.6511 O     -0.6511
HOX    0.0000 HOX    0.4641 HOX2   0.0000 HO11   0.0000 HO11   0.0000
HOX2   0.0000 HOX2   0.0000 HOX    0.4641 HO12   0.0000 HO12   0.0000
$titpair
76 80
$write coord
1000000
$write restart
1000000
$restart
$end