1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
470
471
472
473
474
475
476
477
478
479
480
481
482
483
484
485
486
487
488
489
490
491
492
493
494
495
496
497
498
499
500
501
502
503
504
505
506
507
|
#!/usr/bin/python3
#
# * This library is free software; you can redistribute it and/or
# * modify it under the terms of the GNU Lesser General Public
# * License as published by the Free Software Foundation; either
# * version 2.1 of the License, or (at your option) any later version.
# *
# * This library is distributed in the hope that it will be useful,
# * but WITHOUT ANY WARRANTY; without even the implied warranty of
# * MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU
# * Lesser General Public License for more details.
#
#propka3.0, revision 182 2011-08-09
#-------------------------------------------------------------------------------------------------------
#-- --
#-- PROPKA: A PROTEIN PKA PREDICTOR --
#-- --
#-- VERSION 3.0, 01/01/2011, COPENHAGEN --
#-- BY MATS H.M. OLSSON AND CHRESTEN R. SONDERGARD --
#-- --
#-------------------------------------------------------------------------------------------------------
#
#
#-------------------------------------------------------------------------------------------------------
# References:
#
# Very Fast Empirical Prediction and Rationalization of Protein pKa Values
# Hui Li, Andrew D. Robertson and Jan H. Jensen
# PROTEINS: Structure, Function, and Bioinformatics 61:704-721 (2005)
#
# Very Fast Prediction and Rationalization of pKa Values for Protein-Ligand Complexes
# Delphine C. Bas, David M. Rogers and Jan H. Jensen
# PROTEINS: Structure, Function, and Bioinformatics 73:765-783 (2008)
#
# PROPKA3: Consistent Treatment of Internal and Surface Residues in Empirical pKa predictions
# Mats H.M. Olsson, Chresten R. Sondergard, Michal Rostkowski, and Jan H. Jensen
# Journal of Chemical Theory and Computation, 7, 525-537 (2011)
#-------------------------------------------------------------------------------------------------------
from .vector_algebra import *
from . import bonds, pdb
from .lib import pka_print
class Protonate:
""" Protonates atoms using VSEPR theory """
def __init__(self):
self.valence_electrons = {'H':1,
'C':4,
'N':5,
'O':6,
'F':7,
'P':5,
'S':6,
'CL':7}
self.standard_charges= {'ARG-NH1':1.0,
'ASP-OD2':-1.0,
'GLU-OE2':-1.0,
'HIS-NE2':0.0,
'LYS-NZ':1.0,
'NTERM':1.0,
'CTERM':-1.0}
self.sybyl_charges = {'N.pl3':+1,
'N.3':+1,
'N.4':+1,
'N.ar':+1,
'O.co2+':-1}
# self.standard_conjugate_charges= {'ARG-NH1':1.0}
self.bond_lengths = {'C':1.09,
'N':1.01,
'O':0.96,
'F':0.92,
'Cl':1.27,
'Br':1.41,
'I':1.61}
self.ions = ['NA','CA']
# protonation_methods[steric_number] = method
self.protonation_methods = {4:self.tetrahedral,
3:self.trigonal}
self.my_bond_maker = bonds.bondmaker()
return
def protonate_protein(self, protein):
""" Will protonate all atoms in the protein """
pka_print('----- Protontion started -----')
# Remove all currently present hydrogen atoms
self.remove_all_hydrogen_atoms_from_protein(protein)
# make bonds
self.my_bond_maker.find_bonds_for_protein(protein)
# set charges
self.set_charges(protein)
# protonate all atom
non_H_atoms = []
for chain in protein.chains:
for residue in chain.residues:
if residue.resName.replace(' ','') not in ['N+','C-']:
for atom in residue.atoms:
non_H_atoms.append(atom)
for atom in non_H_atoms:
# if atom.resNumb ==35: #######################
self.protonate_atom(atom)
# fix hydrogen names
self.set_proton_names(non_H_atoms)
return
def protonate_ligand(self, ligand):
""" Will protonate all atoms in the ligand """
pka_print('----- Protontion started -----')
# Remove all currently present hydrogen atoms
self.remove_all_hydrogen_atoms_from_ligand(ligand)
pka_print(ligand)
# make bonds
self.my_bond_maker.find_bonds_for_ligand(ligand)
#import sys
#sys.exit(0)
# set charges
self.set_ligand_charges(ligand)
pka_print('PROTONATING')
# protonate all atoms
atoms = []
for atom in ligand.atoms:
if not atom.get_element() in self.ions:
atoms.append(atom)
for atom in atoms:
self.protonate_atom(atom)
# fix hydrogen names
self.set_proton_names(ligand.atoms)
return
def remove_all_hydrogen_atoms_from_protein(self, protein):
for chain in protein.chains:
for residue in chain.residues:
residue.atoms = [atom for atom in residue.atoms if atom.get_element() != 'H']
return
def remove_all_hydrogen_atoms_from_ligand(self, ligand):
ligand.atoms = [atom for atom in ligand.atoms if atom.get_element() != 'H']
return
def set_ligand_charges(self, ligand, standard_protonation_states = 1):
if standard_protonation_states:
for atom in ligand.atoms:
#pka_print('Charge before', atom, atom.charge)
if atom.name in list(self.sybyl_charges.keys()):
atom.charge = self.sybyl_charges[atom.name]
#pka_print('Charge', atom, atom.charge)
else:
pka_print('Custom protonation state choosen - don\'t know what to do')
return
def set_charges(self, protein, standard_protonation_states = 1):
if standard_protonation_states:
# set side chain charges
for chain in protein.chains:
for residue in chain.residues:
for atom in residue.atoms:
key = '%3s-%s'%(atom.resName, atom.name)
if key in list(self.standard_charges.keys()):
atom.charge = self.standard_charges[key]
pka_print('Charge', atom, atom.charge)
# set n-terminal charges
for chain in protein.chains:
for residue in chain.residues:
if residue.resName.replace(' ','') == 'N+':
for atom in residue.atoms:
if atom.name == 'N':
atom.charge = self.standard_charges['NTERM']
pka_print('Charge', atom, atom.charge)
# set c-terminal charges
for chain in protein.chains:
for residue in chain.residues:
if residue.resName.replace(' ','') == 'C-':
for atom in residue.atoms:
if atom.name in self.my_bond_maker.terminal_oxygen_names:
atom.charge = self.standard_charges['CTERM']
pka_print('Charge', atom, atom.charge)
else:
pka_print('Custom protonation state choosen - don\'t know what to do')
return
def protonate_atom(self, atom):
#print 'protonating atom:',atom.name
#print 'protonating',atom,'with %d bonds'%len(atom.bonded_atoms)
#for ba in atom.bonded_atoms:
# print ' ',ba
self.set_number_of_protons_to_add(atom)
self.set_steric_number_and_lone_pairs(atom)
self.add_protons(atom)
return
def set_proton_names(self, heavy_atoms):
for heavy_atom in heavy_atoms:
i = 1
for bonded in heavy_atom.bonded_atoms:
if bonded.element == 'H':
bonded.name+='%d'%i
i+=1
return
def set_number_of_protons_to_add(self, atom):
pka_print('*'*10)
pka_print('Setting number of protons to add for',atom)
atom.number_of_protons_to_add = 8
pka_print(' %4d'%8)
atom.number_of_protons_to_add -= self.valence_electrons[atom.get_element()]
pka_print('Valence eletrons: %4d'%-self.valence_electrons[atom.get_element()])
atom.number_of_protons_to_add -= len(atom.bonded_atoms)
pka_print('Number of bonds: %4d'%- len(atom.bonded_atoms))
atom.number_of_protons_to_add -= atom.number_of_pi_electrons_in_double_and_triple_bonds
pka_print('Pi electrons: %4d'%-atom.number_of_pi_electrons_in_double_and_triple_bonds)
atom.number_of_protons_to_add += int(atom.charge)
pka_print('Charge: %4.1f'%atom.charge)
pka_print('-'*10)
pka_print(atom.number_of_protons_to_add)
return
def set_steric_number_and_lone_pairs(self, atom):
pka_print('='*10)
pka_print('Setting steric number and lone pairs for',atom)
# costumly set the N backbone atoms up for peptide bond trigonal planer shape
#if atom.name == 'N' and len(atom.bonded_atoms) == 2:
# atom.steric_number = 3
# atom.number_of_lone_pairs = 0
# print 'Peptide bond: steric number is %d and number of lone pairs is %s'%(atom.steric_number,
# atom.number_of_lone_pairs)
# return
atom.steric_number = 0
pka_print('%65s: %4d'%('Valence electrons',self.valence_electrons[atom.get_element()]))
atom.steric_number += self.valence_electrons[atom.get_element()]
pka_print('%65s: %4d'%('Number of bonds',len(atom.bonded_atoms)))
atom.steric_number += len(atom.bonded_atoms)
pka_print('%65s: %4d'%('Number of hydrogen atoms to add',atom.number_of_protons_to_add))
atom.steric_number += atom.number_of_protons_to_add
pka_print('%65s: %4d'%('Number of pi-electrons in double and triple bonds(-)',atom.number_of_pi_electrons_in_double_and_triple_bonds))
atom.steric_number -= atom.number_of_pi_electrons_in_double_and_triple_bonds
pka_print('%65s: %4d'%('Number of pi-electrons in conjugated double and triple bonds(-)',atom.number_of_pi_electrons_in_conjugate_double_and_triple_bonds))
atom.steric_number -= atom.number_of_pi_electrons_in_conjugate_double_and_triple_bonds
pka_print('%65s: %4d'%('Number of donated co-ordinated bonds',0))
atom.steric_number += 0
pka_print('%65s: %4.1f'%('Charge(-)',atom.charge))
atom.steric_number -= atom.charge
atom.steric_number = math.floor(atom.steric_number/2.0)
atom.number_of_lone_pairs = atom.steric_number - len(atom.bonded_atoms) - atom.number_of_protons_to_add
pka_print('-'*70)
pka_print('%65s: %4d'%('Steric number',atom.steric_number))
pka_print('%65s: %4d'%('Number of lone pairs',atom.number_of_lone_pairs))
return
def add_protons(self, atom):
# decide which method to use
pka_print('PROTONATING',atom)
if atom.steric_number in list(self.protonation_methods.keys()):
self.protonation_methods[atom.steric_number](atom)
else:
pka_print('Warning: Do not have a method for protonating',atom,'(steric number: %d)'%atom.steric_number)
return
def trigonal(self, atom):
pka_print('TRIGONAL - %d bonded atoms'%(len(atom.bonded_atoms)))
rot_angle = math.radians(120.0)
c = multi_vector(atom1 = atom)
# 0 bonds
if len(atom.bonded_atoms) == 0:
pass
# 1 bond
if len(atom.bonded_atoms) == 1 and atom.number_of_protons_to_add > 0:
# Add another atom with the right angle to the first one
a = multi_vector(atom1 = atom, atom2 = atom.bonded_atoms[0])
# use plane of bonded trigonal atom - e.g. arg
if atom.bonded_atoms[0].steric_number == 3 and len(atom.bonded_atoms[0].bonded_atoms)>1:
# use other atoms bonded to the neighbour to establish the plane, if possible
other_atom_indices = []
for i in range(len(atom.bonded_atoms[0].bonded_atoms)):
if atom.bonded_atoms[0].bonded_atoms[i] != atom:
other_atom_indices.append(i)
if len(other_atom_indices)<2:
other_atom_indices = [0,1]
axis = multi_vector(atom1 = atom.bonded_atoms[0],
atom2 = atom.bonded_atoms[0].bonded_atoms[other_atom_indices[0]]
)**multi_vector(atom1 = atom.bonded_atoms[0],
atom2 = atom.bonded_atoms[0].bonded_atoms[other_atom_indices[1]])
else:
axis = a.orthogonal()
a = rotate_multi_vector_around_an_axis(rot_angle, axis, a)
a = self.set_bond_distance(a, atom.get_element())
self.add_proton(atom, c+a)
# 2 bonds
if len(atom.bonded_atoms) == 2 and atom.number_of_protons_to_add > 0:
# Add another atom with the right angle to the first two
a = multi_vector(atom1 = atom, atom2 = atom.bonded_atoms[1])
b = multi_vector(atom1 = atom, atom2 = atom.bonded_atoms[0])
axis = b**a
new_a = rotate_multi_vector_around_an_axis(rot_angle, axis, a)
new_a = self.set_bond_distance(new_a, atom.get_element())
self.add_proton(atom, c+new_a)
return
def tetrahedral(self, atom):
pka_print('TETRAHEDRAL - %d bonded atoms'%(len(atom.bonded_atoms)))
rot_angle = math.radians(109.5)
# sanity check
# if atom.number_of_protons_to_add + len(atom.bonded_atoms) != 4:
# print 'Error: Attempting tetrahedral structure with %d bonds'%(atom.number_of_protons_to_add +
# len(atom.bonded_atoms))
c = multi_vector(atom1 = atom)
# 0 bonds
if len(atom.bonded_atoms) == 0:
pass
# 1 bond
if len(atom.bonded_atoms) == 1 and atom.number_of_protons_to_add > 0:
# Add another atom with the right angle to the first one
a = multi_vector(atom1 = atom, atom2 = atom.bonded_atoms[0])
axis = a.orthogonal()
a = rotate_multi_vector_around_an_axis(rot_angle, axis, a)
a = self.set_bond_distance(a, atom.get_element())
self.add_proton(atom, c+a)
# 2 bonds
if len(atom.bonded_atoms) == 2 and atom.number_of_protons_to_add > 0:
# Add another atom with the right angle to the first two
a = multi_vector(atom1 = atom, atom2 = atom.bonded_atoms[1])
axis = multi_vector(atom1 = atom.bonded_atoms[0],atom2 = atom)
new_a = rotate_multi_vector_around_an_axis(math.radians(120), axis, a)
new_a = self.set_bond_distance(new_a, atom.get_element())
self.add_proton(atom, c+new_a)
# 3 bonds
if len(atom.bonded_atoms) == 3 and atom.number_of_protons_to_add > 0:
a = multi_vector(atom1 = atom, atom2 = atom.bonded_atoms[2])
axis = multi_vector(atom1 = atom.bonded_atoms[0],atom2 = atom)
b = multi_vector(atom1 = atom, atom2 = atom.bonded_atoms[1])
cross = b**axis
angle = math.radians(120)
if angle_degrees(cross.vectors[0],a.vectors[0]) < 90:
angle = -angle
new_a = rotate_multi_vector_around_an_axis(angle, axis, a)
new_a = self.set_bond_distance(new_a, atom.get_element())
self.add_proton(atom, c+new_a)
return
def add_proton(self, atom, position):
residue = atom.residue
#pka_print(residue)
# Create the new proton
new_H = pdb.Atom()
new_H.setProperty(numb = None,
name = 'H',
resName = atom.resName,
chainID = atom.chainID,
resNumb = atom.resNumb,
x = None,
y = None,
z = None,
occ = None,
beta = None)
new_H.element = 'H'
pka_print(position)
# set all the configurations
for i in range(len(position.keys)):
#print ('adding',position.keys[i],position.vectors[i])
new_H.configurations[position.keys[i]] = [position.vectors[i].x,
position.vectors[i].y,
position.vectors[i].z]
new_H.setConfiguration(position.keys[0])
new_H.bonded_atoms = []
new_H.charge = 0
new_H.steric_number = 0
new_H.number_of_lone_pairs = 0
new_H.number_of_protons_to_add = 0
new_H.number_of_pi_electrons_in_double_and_triple_bonds = 0
residue.atoms.append(new_H)
atom.bonded_atoms.append(new_H)
atom.number_of_protons_to_add -=1
pka_print('added',new_H, 'to',atom)
return
def set_bond_distance(self, a, element):
d = 1.0
if element in list(self.bond_lengths.keys()):
d = self.bond_lengths[element]
else:
pka_print('WARNING: Bond length for %s not found, using the standard value of %f'%(element, d))
a = a.rescale(d)
return a
if __name__ == '__main__':
import protein, pdb, sys,os
arguments = sys.argv
if len(arguments) != 2:
pka_print('Usage: protonate.py <pdb_file>')
sys.exit(0)
filename = arguments[1]
if not os.path.isfile(filename):
pka_print('Error: Could not find \"%s\"'%filename)
sys.exit(1)
p = Protonate()
pdblist = pdb.readPDB(filename)
my_protein = protein.Protein(pdblist,'test.pdb')
p.remove_all_hydrogen_atoms_from_protein(my_protein)
my_protein.writePDB('before_protonation.pdb')
p.protonate_protein(my_protein)
## write out protonated file
my_protein.writePDB('protonated.pdb')
|
