File: MolFileStereochem.cpp

package info (click to toggle)
rdkit 201809.1%2Bdfsg-6
  • links: PTS, VCS
  • area: main
  • in suites: buster
  • size: 123,688 kB
  • sloc: cpp: 230,509; python: 70,501; java: 6,329; ansic: 5,427; sql: 1,899; yacc: 1,739; lex: 1,243; makefile: 445; xml: 229; fortran: 183; sh: 123; cs: 93
file content (710 lines) | stat: -rw-r--r-- 25,959 bytes parent folder | download
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
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
554
555
556
557
558
559
560
561
562
563
564
565
566
567
568
569
570
571
572
573
574
575
576
577
578
579
580
581
582
583
584
585
586
587
588
589
590
591
592
593
594
595
596
597
598
599
600
601
602
603
604
605
606
607
608
609
610
611
612
613
614
615
616
617
618
619
620
621
622
623
624
625
626
627
628
629
630
631
632
633
634
635
636
637
638
639
640
641
642
643
644
645
646
647
648
649
650
651
652
653
654
655
656
657
658
659
660
661
662
663
664
665
666
667
668
669
670
671
672
673
674
675
676
677
678
679
680
681
682
683
684
685
686
687
688
689
690
691
692
693
694
695
696
697
698
699
700
701
702
703
704
705
706
707
708
709
710
//
//  Copyright (C) 2004-2017 Greg Landrum and Rational Discovery LLC
//
//   @@ All Rights Reserved @@
//  This file is part of the RDKit.
//  The contents are covered by the terms of the BSD license
//  which is included in the file license.txt, found at the root
//  of the RDKit source tree.
//
//
#include <list>
#include <RDGeneral/RDLog.h>
#include "MolFileStereochem.h"
#include <Geometry/point.h>
#include <boost/dynamic_bitset.hpp>
#include <algorithm>
#include "MolFileStereochem.h"
#include <RDGeneral/Ranking.h>

namespace RDKit {
typedef std::list<double> DOUBLE_LIST;

// ----------------------------------- -----------------------------------
// This algorithm is identical to that used in the CombiCode Mol file
//  parser (also developed by RD).
//
//
// SUMMARY:
//   Derive a chiral code for an atom that has a wedged (or dashed) bond
//   drawn to it.
//
// RETURNS:
//   The chiral type
//
// CAVEATS:
//   This is careful to ensure that the central atom has 4 neighbors and
//   only single bonds to it, but that's about it.
//
// NOTE: this isn't careful at all about checking to make sure that
// things actually *should* be chiral. e.g. if the file has a
// 3-coordinate N with a wedged bond, it will make some erroneous
// assumptions about the chirality.
//
// ----------------------------------- -----------------------------------

Atom::ChiralType FindAtomStereochemistry(const RWMol &mol, const Bond *bond,
                                         const Conformer *conf) {
  PRECONDITION(bond, "no bond");
  PRECONDITION(conf, "no conformer");
  Bond::BondDir bondDir = bond->getBondDir();
  PRECONDITION(bondDir == Bond::BEGINWEDGE || bondDir == Bond::BEGINDASH,
               "bad bond direction");

  // NOTE that according to the CT file spec, wedging assigns chirality
  // to the atom at the point of the wedge, (atom 1 in the bond).
  const Atom *atom = bond->getBeginAtom();
  PRECONDITION(atom, "no atom");

  // we can't do anything with atoms that have more than 4 neighbors:
  if (atom->getDegree() > 4) {
    return Atom::CHI_UNSPECIFIED;
  }
  const Atom *bondAtom = bond->getEndAtom();

  Atom::ChiralType res = Atom::CHI_UNSPECIFIED;

  INT_LIST neighborBondIndices;
  RDGeom::Point3D centerLoc, tmpPt;
  centerLoc = conf->getAtomPos(atom->getIdx());
  tmpPt = conf->getAtomPos(bondAtom->getIdx());
  centerLoc.z = 0.0;
  tmpPt.z = 0.0;

  RDGeom::Point3D refVect = centerLoc.directionVector(tmpPt);

  //----------------------------------------------------------
  //
  //  start by ensuring that all the bonds to neighboring atoms
  //  are single bonds and collecting a list of neighbor indices:
  //
  //----------------------------------------------------------
  bool hSeen = false;

  neighborBondIndices.push_back(bond->getIdx());
  if (bondAtom->getAtomicNum() == 1 && bondAtom->getIsotope() == 0)
    hSeen = true;

  bool allSingle = true;
  ROMol::OEDGE_ITER beg, end;
  boost::tie(beg, end) = mol.getAtomBonds(atom);
  while (beg != end) {
    const Bond *nbrBond = mol[*beg];
    if (nbrBond->getBondType() != Bond::SINGLE) {
      allSingle = false;
      // break;
    }
    if (nbrBond != bond) {
      if ((nbrBond->getOtherAtom(atom)->getAtomicNum() == 1 &&
           nbrBond->getOtherAtom(atom)->getIsotope() == 0))
        hSeen = true;
      neighborBondIndices.push_back(nbrBond->getIdx());
    }
    ++beg;
  }
  size_t nNbrs = neighborBondIndices.size();

  //----------------------------------------------------------
  //
  //  Return now if there aren't at least 3 non-H bonds to the atom.
  //  (we can implicitly add a single H to 3 coordinate atoms, but
  //  we're horked otherwise).
  //
  //----------------------------------------------------------
  if (nNbrs < 3 || (hSeen && nNbrs < 4)) {
    return Atom::CHI_UNSPECIFIED;
  }

  //----------------------------------------------------------
  //
  //  Continue if there are all single bonds or if we're considering
  //  4-coordinate P or S
  //
  //----------------------------------------------------------
  if (allSingle || atom->getAtomicNum() == 15 || atom->getAtomicNum() == 16) {
    //------------------------------------------------------------
    //
    //  Here we need to figure out the rotation direction between
    //  the neighbor bonds and the wedged bond:
    //
    //------------------------------------------------------------
    bool isCCW = true;
    double angle0, angle1, angle2;
    const Bond *bond1, *bond2, *bond3;
    RDGeom::Point3D atomVect0, atomVect1, atomVect2;
    INT_LIST::const_iterator bondIter = neighborBondIndices.begin();
    ++bondIter;
    bond1 = mol.getBondWithIdx(*bondIter);
    int oaid = bond1->getOtherAtom(atom)->getIdx();
    tmpPt = conf->getAtomPos(oaid);
    tmpPt.z = 0;
    atomVect0 = centerLoc.directionVector(tmpPt);
    angle0 = refVect.signedAngleTo(atomVect0);
    if (angle0 < 0) angle0 += 2. * M_PI;

    ++bondIter;
    bond2 = mol.getBondWithIdx(*bondIter);
    oaid = bond2->getOtherAtom(atom)->getIdx();
    tmpPt = conf->getAtomPos(oaid);
    tmpPt.z = 0;
    atomVect1 = centerLoc.directionVector(tmpPt);
    angle1 = refVect.signedAngleTo(atomVect1);
    if (angle1 < 0) angle1 += 2. * M_PI;

    // We proceed differently for 3 and 4 coordinate atoms:
    double firstAngle, secondAngle;
    if (nNbrs == 4) {
      bool flipIt = false;
      // grab the angle to the last neighbor:
      ++bondIter;
      bond3 = mol.getBondWithIdx(*bondIter);
      oaid = bond3->getOtherAtom(atom)->getIdx();
      tmpPt = conf->getAtomPos(oaid);
      tmpPt.z = 0;
      atomVect2 = centerLoc.directionVector(tmpPt);
      angle2 = refVect.signedAngleTo(atomVect2);
      if (angle2 < 0) angle2 += 2. * M_PI;

      // find the lowest and second-lowest angle and keep track of
      // whether or not we have to do a non-cyclic permutation to
      // get there:
      if (angle0 < angle1) {
        if (angle1 < angle2) {
          // order is angle0 -> angle1 -> angle2
          firstAngle = angle0;
          secondAngle = angle1;
        } else if (angle0 < angle2) {
          // order is angle0 -> angle2 -> angle1
          firstAngle = angle0;
          secondAngle = angle2;
          flipIt = true;
        } else {
          // order is angle2 -> angle0 -> angle1
          firstAngle = angle2;
          secondAngle = angle0;
        }
      } else if (angle0 < angle2) {
        // order is angle1 -> angle0 -> angle2
        firstAngle = angle1;
        secondAngle = angle0;
        flipIt = true;
      } else {
        if (angle1 < angle2) {
          // order is angle1 -> angle2 -> angle0
          firstAngle = angle1;
          secondAngle = angle2;
        } else {
          // order is angle2 -> angle1 -> angle0
          firstAngle = angle2;
          secondAngle = angle1;
          flipIt = true;
        }
      }
      if (flipIt) {
        isCCW = !isCCW;
      }
    } else {
      // it's three coordinate.  Things are a bit different here
      // because we have to at least kind of figure out where the
      // hydrogen might be.

      // before getting started with that, use some of the inchi rules
      // for contradictory stereochemistry
      // (Table 10 in the InChi v1 technical manual)

      angle2 = atomVect0.signedAngleTo(atomVect1);
      if (angle2 < 0) angle2 += 2. * M_PI;

      //  this one is never allowed:
      //     0   2
      //      \ /
      //       C
      //       *
      //       1
      if (angle0 < (M_PI - 1e-3) && angle1 < (M_PI - 1e-3) &&
          angle2 < (M_PI - 1e-3)) {
        if ((bond1->getBondDir() != Bond::NONE &&
             bond1->getBeginAtomIdx() == bond->getBeginAtomIdx() &&
             (bond1->getBondDir() != bond->getBondDir() ||
              (bond2->getBondDir() != Bond::NONE &&
               bond2->getBeginAtomIdx() == bond->getBeginAtomIdx() &&
               bond2->getBondDir() != bond1->getBondDir()))) ||
            (bond2->getBondDir() != Bond::NONE &&
             bond2->getBeginAtomIdx() == bond->getBeginAtomIdx() &&
             bond2->getBondDir() != bond->getBondDir())) {
          BOOST_LOG(rdWarningLog)
              << "Warning: conflicting stereochemistry at atom "
              << bond->getBeginAtomIdx() << " ignored."
              << std::endl;  // by rule 1." << std::endl;
          return Atom::CHI_UNSPECIFIED;
        }
      }
      if (bond1->getBondDir() != Bond::NONE &&
          bond1->getBeginAtomIdx() == bond->getBeginAtomIdx()) {
        if (!(bond2->getBondDir() != Bond::NONE &&
              bond2->getBeginAtomIdx() == bond->getBeginAtomIdx())) {
          BOOST_LOG(rdWarningLog)
              << "Warning: conflicting stereochemistry at atom "
              << bond->getBeginAtomIdx() << " ignored."
              << std::endl;  // by rule 2a." << std::endl;
        }
        if (bond1->getBondDir() != bond->getBondDir()) {
          // bond1 has a spec and does not match the bond0 spec.
          // the only cases this is allowed are:
          //      1        0 1 2
          //      *         \*/
          //  0 - C - 2      C
          //    and
          //      1        2 1 0
          //      *         \*/
          //  2 - C - 0      C
          //
          if ((angle0 > M_PI && angle0 < angle1) ||
              (angle0 < M_PI && angle0 > angle1)) {
            BOOST_LOG(rdWarningLog)
                << "Warning: conflicting stereochemistry at atom "
                << bond->getBeginAtomIdx() << " ignored."
                << std::endl;  // by rule 2b." << std::endl;
            return Atom::CHI_UNSPECIFIED;
          }
        } else {
          // bond1 matches, what about bond2 ?
          if (bond2->getBondDir() != bond->getBondDir()) {
            // the only cases this is allowed are:
            //      2        0 2 1
            //      *         \*/
            //  0 - C - 1      C
            //    and
            //      2        1 2 0
            //      *         \*/
            //  1 - C - 0      C
            //
            if ((angle1 > M_PI && angle1 < angle0) ||
                (angle1 < M_PI && angle1 > angle0)) {
              BOOST_LOG(rdWarningLog)
                  << "Warning: conflicting stereochemistry at atom "
                  << bond->getBeginAtomIdx() << " ignored."
                  << std::endl;  // by rule 2c." << std::endl;
              return Atom::CHI_UNSPECIFIED;
            }
          }
        }
      } else if (bond2->getBondDir() != Bond::NONE &&
                 bond2->getBeginAtomIdx() == bond->getBeginAtomIdx() &&
                 bond2->getBondDir() != bond->getBondDir()) {
        // bond2 has a spec and does not match the bond0 spec, but bond1
        // is not set: this is never allowed.
        BOOST_LOG(rdWarningLog)
            << "Warning: conflicting stereochemistry at atom "
            << bond->getBeginAtomIdx() << " ignored."
            << std::endl;  // by rule 3." << std::endl;
        return Atom::CHI_UNSPECIFIED;
      }

      if (angle0 < angle1) {
        firstAngle = angle0;
        secondAngle = angle1;
        isCCW = true;
      } else {
        firstAngle = angle1;
        secondAngle = angle0;
        isCCW = false;
      }
      if (secondAngle - firstAngle >= (M_PI - 1e-4)) {
        // it's a situation like one of these:
        //
        //      0        1 0 2
        //      *         \*/
        //  1 - C - 2      C
        //
        // In each of these cases, the implicit H is between atoms 1
        // and 2, so we need to flip the rotation direction (go
        // around the back).
        isCCW = !isCCW;
      }
    }
    // reverse the rotation direction if the reference is wedged down:
    if (bondDir == Bond::BEGINDASH) {
      isCCW = !isCCW;
    }

    // ----------------
    //
    // We now have the rotation direction using mol-file order.
    // We need to convert that into the appropriate label for the
    // central atom
    //
    // ----------------
    int nSwaps = atom->getPerturbationOrder(neighborBondIndices);
    if (nSwaps % 2) isCCW = !isCCW;
    if (isCCW)
      res = Atom::CHI_TETRAHEDRAL_CCW;
    else
      res = Atom::CHI_TETRAHEDRAL_CW;
  }

  return res;
}

void WedgeBond(Bond *bond, unsigned int fromAtomIdx, const Conformer *conf) {
  PRECONDITION(bond, "no bond");
  PRECONDITION(conf, "no conformer");
  PRECONDITION(&conf->getOwningMol() == &bond->getOwningMol(),"bond and conformer do not belong to same molecule");
  if(bond->getBondType() != Bond::SINGLE) return;
  Bond::BondDir dir = DetermineBondWedgeState(bond, fromAtomIdx, conf);
  if (dir == Bond::BEGINWEDGE || dir == Bond::BEGINDASH) {
    bond->setBondDir(dir);
  }
}

void WedgeMolBonds(ROMol &mol, const Conformer *conf) {
  PRECONDITION(conf, "no conformer");
  INT_MAP_INT wedgeBonds = pickBondsToWedge(mol);
  for (ROMol::BondIterator bondIt = mol.beginBonds(); bondIt != mol.endBonds();
       ++bondIt) {
    Bond *bond = *bondIt;
    if (bond->getBondType() == Bond::SINGLE) {
      Bond::BondDir dir = DetermineBondWedgeState(bond, wedgeBonds, conf);
      if (dir == Bond::BEGINWEDGE || dir == Bond::BEGINDASH) {
        bond->setBondDir(dir);
      }
    }
  }
}

INT_MAP_INT pickBondsToWedge(const ROMol &mol) {
  // we need ring information; make sure findSSSR has been called before
  // if not call now
  if (!mol.getRingInfo()->isInitialized()) {
    MolOps::findSSSR(mol);
  }

  static int noNbrs = 100;
  INT_VECT nChiralNbrs(mol.getNumAtoms(), noNbrs);

  // start by looking for bonds that are already wedged
  for (ROMol::ConstBondIterator cbi = mol.beginBonds(); cbi != mol.endBonds();
       ++cbi) {
    const Bond *bond = *cbi;
    if (bond->getBondDir() == Bond::BEGINWEDGE ||
        bond->getBondDir() == Bond::BEGINDASH ||
        bond->getBondDir() == Bond::UNKNOWN) {
      if (bond->getBeginAtom()->getChiralTag() == Atom::CHI_TETRAHEDRAL_CW ||
          bond->getBeginAtom()->getChiralTag() == Atom::CHI_TETRAHEDRAL_CCW)
        nChiralNbrs[bond->getBeginAtomIdx()] = noNbrs + 1;
      else if (bond->getEndAtom()->getChiralTag() == Atom::CHI_TETRAHEDRAL_CW ||
               bond->getEndAtom()->getChiralTag() == Atom::CHI_TETRAHEDRAL_CCW)
        nChiralNbrs[bond->getEndAtomIdx()] = noNbrs + 1;
    }
  }

  // now rank atoms by the number of chiral neighbors or Hs they have:
  bool chiNbrs = false;
  for (ROMol::ConstAtomIterator cai = mol.beginAtoms(); cai != mol.endAtoms();
       ++cai) {
    const Atom *at = *cai;
    if (nChiralNbrs[at->getIdx()] > noNbrs) {
      // std::cerr << " SKIPPING1: " << at->getIdx() << std::endl;
      continue;
    }
    Atom::ChiralType type = at->getChiralTag();
    if (type != Atom::CHI_TETRAHEDRAL_CW && type != Atom::CHI_TETRAHEDRAL_CCW)
      continue;
    nChiralNbrs[at->getIdx()] = 0;
    chiNbrs = true;
    ROMol::ADJ_ITER nbrIdx, endNbrs;
    boost::tie(nbrIdx, endNbrs) = mol.getAtomNeighbors(at);
    while (nbrIdx != endNbrs) {
      const Atom* nat = mol[*nbrIdx];
      ++nbrIdx;
      if (nat->getAtomicNum() == 1) {
        // special case: it's an H... we weight these especially high:
        nChiralNbrs[at->getIdx()] -= 10;
        continue;
      }
      type = nat->getChiralTag();
      if (type != Atom::CHI_TETRAHEDRAL_CW && type != Atom::CHI_TETRAHEDRAL_CCW)
        continue;
      nChiralNbrs[at->getIdx()] -= 1;
    }
  }
  std::vector<unsigned int> indices(mol.getNumAtoms());
  for (unsigned int i = 0; i < mol.getNumAtoms(); ++i) indices[i] = i;
  if (chiNbrs) {
    std::sort(indices.begin(), indices.end(),
              Rankers::argless<INT_VECT>(nChiralNbrs));
  }
#if 0
  std::cerr << "  nbrs: ";
  std::copy(nChiralNbrs.begin(), nChiralNbrs.end(),
            std::ostream_iterator<int>(std::cerr, " "));
  std::cerr << std::endl;
  std::cerr << "  order: ";
  std::copy(indices.begin(), indices.end(),
            std::ostream_iterator<int>(std::cerr, " "));
  std::cerr << std::endl;
#endif
  // picks a bond for each atom that we will wedge when we write the mol file
  // here is what we are going to do
  // - at each chiral center look for a bond that is begins at the atom and
  //   is not yet picked to be wedged for a different chiral center, preferring
  //   bonds to Hs
  // - if we do not find a bond that begins at the chiral center - we will take
  //   the first bond that is not yet picked by any other chiral centers
  // we use the orders calculated above to determine which order to do the
  // wedging
  INT_MAP_INT res;
  BOOST_FOREACH (unsigned int idx, indices) {
    if (nChiralNbrs[idx] > noNbrs) {
      // std::cerr << " SKIPPING2: " << idx << std::endl;
      continue;  // already have a wedged bond here
    }
    const Atom *atom = mol.getAtomWithIdx(idx);
    Atom::ChiralType type = atom->getChiralTag();
    // the indices are ordered such that all chiral atoms come first. If
    // this has no chiral flag, we can stop the whole loop:
    if (type != Atom::CHI_TETRAHEDRAL_CW && type != Atom::CHI_TETRAHEDRAL_CCW)
      break;
    RDKit::ROMol::OBOND_ITER_PAIR atomBonds = mol.getAtomBonds(atom);
    std::vector<std::pair<int, int>> nbrScores;
    while (atomBonds.first != atomBonds.second) {
      const Bond *bond = mol[*atomBonds.first];
      ++atomBonds.first;

      // can only wedge single bonds:
      if (bond->getBondType() != Bond::SINGLE) continue;

      int bid = bond->getIdx();
      if (res.find(bid) == res.end()) {
        // very strong preference for Hs:
        if (bond->getOtherAtom(atom)->getAtomicNum() == 1) {
          nbrScores.push_back(std::make_pair(
              -1000000, bid));  // lower than anything else can be
          continue;
        }
        // prefer lower atomic numbers with lower degrees and no specified
        // chirality:
        const Atom *oatom = bond->getOtherAtom(atom);
        int nbrScore = oatom->getAtomicNum() + 10 * oatom->getDegree() +
                       100 * ((oatom->getChiralTag() != Atom::CHI_UNSPECIFIED));
        // prefer neighbors that are nonchiral or have as few chiral neighbors
        // as possible:
        int oIdx = oatom->getIdx();
        if (nChiralNbrs[oIdx] < noNbrs) {
          // the counts are negative, so we have to subtract them off
          nbrScore -= 10000 * nChiralNbrs[oIdx];
        }
        // prefer bonds to non-ring atoms:
        nbrScore += 1000 * mol.getRingInfo()->numAtomRings(oIdx);
        // prefer non-ring bonds;
        nbrScore += 1000 * mol.getRingInfo()->numBondRings(bid);
        // std::cerr << "    nrbScore: " << idx << " - " << oIdx << " : "
        //           << nbrScore << " nChiralNbrs: " << nChiralNbrs[oIdx]
        //           << std::endl;
        nbrScores.push_back(std::make_pair(nbrScore, bid));
      }
    }
    // There's still one situation where this whole thing can fail: an unlucky
    // situation where all neighbors of all neighbors of an atom are chiral and
    // that atom ends up being the last one picked for stereochem assignment.
    //
    // We'll catch that as an error here and hope that it's as unlikely to occur
    // as it seems like it is. (I'm going into this knowing that it's bound to
    // happen; I'll kick myself and do the hard solution at that point.)
    CHECK_INVARIANT(nbrScores.size(),
                    "no eligible neighbors for chiral center");
    std::sort(nbrScores.begin(), nbrScores.end(),
              Rankers::pairLess<int, int>());
    res[nbrScores[0].second] = idx;
  }
  return res;
}

//
// Determine bond wedge state
///
Bond::BondDir DetermineBondWedgeState(const Bond *bond,
                                      unsigned int fromAtomIdx,
                                      const Conformer *conf) {
  PRECONDITION(bond, "no bond");
  PRECONDITION(bond->getBondType() == Bond::SINGLE,
               "bad bond order for wedging");
   const ROMol *mol = &(bond->getOwningMol());
   PRECONDITION(mol, "no mol");

   Bond::BondDir res = bond->getBondDir();
   if (!conf) {
     return res;
   }


   Atom *atom, *bondAtom;  // = bond->getBeginAtom();
   if (bond->getBeginAtom()->getIdx() == fromAtomIdx) {
     atom = bond->getBeginAtom();
     bondAtom = bond->getEndAtom();
   } else {
     atom = bond->getEndAtom();
     bondAtom = bond->getBeginAtom();
   }

   Atom::ChiralType chiralType = atom->getChiralTag();
   CHECK_INVARIANT(chiralType == Atom::CHI_TETRAHEDRAL_CW ||
                       chiralType == Atom::CHI_TETRAHEDRAL_CCW,
                   "");

   // if we got this far, we really need to think about it:
   INT_LIST neighborBondIndices;
   DOUBLE_LIST neighborBondAngles;
   RDGeom::Point3D centerLoc, tmpPt;
   centerLoc = conf->getAtomPos(atom->getIdx());
   tmpPt = conf->getAtomPos(bondAtom->getIdx());
   centerLoc.z = 0.0;
   tmpPt.z = 0.0;
   RDGeom::Point3D refVect = centerLoc.directionVector(tmpPt);

   neighborBondIndices.push_back(bond->getIdx());
   neighborBondAngles.push_back(0.0);

   ROMol::OEDGE_ITER beg, end;
   boost::tie(beg, end) = mol->getAtomBonds(atom);
   while (beg != end) {
     const Bond *nbrBond = (*mol)[*beg];
     Atom *otherAtom = nbrBond->getOtherAtom(atom);
     if (nbrBond != bond) {
       tmpPt = conf->getAtomPos(otherAtom->getIdx());
       tmpPt.z = 0.0;
       RDGeom::Point3D tmpVect = centerLoc.directionVector(tmpPt);
       double angle = refVect.signedAngleTo(tmpVect);
       if (angle < 0.0) angle += 2. * M_PI;
       auto nbrIt = neighborBondIndices.begin();
       auto angleIt = neighborBondAngles.begin();
       // find the location of this neighbor in our angle-sorted list
       // of neighbors:
       while (angleIt != neighborBondAngles.end() && angle > (*angleIt)) {
         ++angleIt;
         ++nbrIt;
       }
       neighborBondAngles.insert(angleIt, angle);
       neighborBondIndices.insert(nbrIt, nbrBond->getIdx());
     }
     ++beg;
   }

   // at this point, neighborBondIndices contains a list of bond
   // indices from the central atom.  They are arranged starting
   // at the reference bond in CCW order (based on the current
   // depiction).
   int nSwaps = atom->getPerturbationOrder(neighborBondIndices);

   // in the case of three-coordinated atoms we may have to worry about
   // the location of the implicit hydrogen - Issue 209
   // Check if we have one of these situation
   //
   //      0        1 0 2
   //      *         \*/
   //  1 - C - 2      C
   //
   // here the hydrogen will be between 1 and 2 and we need to add an additional
   // swap
   if (neighborBondAngles.size() == 3) {
     // three coordinated
     auto angleIt = neighborBondAngles.begin();
     ++angleIt;  // the first is the 0 (or reference bond - we will ignoire that
     double angle1 = (*angleIt);
     ++angleIt;
     double angle2 = (*angleIt);
     if (angle2 - angle1 >= (M_PI - 1e-4)) {
       // we have the above situation
       nSwaps++;
     }
   }

 #ifdef VERBOSE_STEREOCHEM
   BOOST_LOG(rdDebugLog) << "--------- " << nSwaps << std::endl;
   std::copy(neighborBondIndices.begin(), neighborBondIndices.end(),
             std::ostream_iterator<int>(BOOST_LOG(rdDebugLog), " "));
   BOOST_LOG(rdDebugLog) << std::endl;
   std::copy(neighborBondAngles.begin(), neighborBondAngles.end(),
             std::ostream_iterator<double>(BOOST_LOG(rdDebugLog), " "));
   BOOST_LOG(rdDebugLog) << std::endl;
 #endif
   if (chiralType == Atom::CHI_TETRAHEDRAL_CCW) {
     if (nSwaps % 2 == 1) {  // ^ reverse) {
       res = Bond::BEGINDASH;
     } else {
       res = Bond::BEGINWEDGE;
     }
   } else {
     if (nSwaps % 2 == 1) {  // ^ reverse) {
       res = Bond::BEGINWEDGE;
     } else {
       res = Bond::BEGINDASH;
     }
   }

   return res;
}
Bond::BondDir DetermineBondWedgeState(const Bond *bond,
                                      const INT_MAP_INT &wedgeBonds,
                                      const Conformer *conf) {
  PRECONDITION(bond, "no bond");
  int bid = bond->getIdx();
  auto wbi = wedgeBonds.find(bid);
  if (wbi == wedgeBonds.end()) {
    return bond->getBondDir();
  }

  unsigned int waid = wbi->second;
  return DetermineBondWedgeState(bond,waid,conf);
}

// handles stereochem markers set by the Mol file parser and
// converts them to the RD standard:
void DetectAtomStereoChemistry(RWMol &mol, const Conformer *conf) {
  PRECONDITION(conf, "no conformer");

  for (RWMol::BondIterator bondIt = mol.beginBonds(); bondIt != mol.endBonds();
       ++bondIt) {
    Bond *bond = *bondIt;
    if (bond->getBondDir() != Bond::UNKNOWN) {
      Bond::BondDir dir = bond->getBondDir();
      // the bond is marked as chiral:
      if (dir == Bond::BEGINWEDGE || dir == Bond::BEGINDASH) {
        Atom *atom = bond->getBeginAtom();
        if (atom->getImplicitValence() == -1) {
          atom->calcExplicitValence(false);
          atom->calcImplicitValence(false);
        }
        Atom::ChiralType code = FindAtomStereochemistry(mol, bond, conf);
        atom->setChiralTag(code);
        // within the RD representation, if a three-coordinate atom
        // is chiral and has an implicit H, that H needs to be made explicit:
        if (atom->getDegree() == 3 && !atom->getNumExplicitHs() &&
            atom->getNumImplicitHs() == 1) {
          atom->setNumExplicitHs(1);
          // recalculated number of implicit Hs:
          atom->updatePropertyCache();
        }
      }
    }
  }
}

void ClearSingleBondDirFlags(ROMol &mol) {
  for (RWMol::BondIterator bondIt = mol.beginBonds(); bondIt != mol.endBonds();
       ++bondIt) {
    if ((*bondIt)->getBondType() == Bond::SINGLE) {
      if ((*bondIt)->getBondDir() == Bond::UNKNOWN)
        (*bondIt)->setProp(common_properties::_UnknownStereo, 1);
      (*bondIt)->setBondDir(Bond::NONE);
    }
  }
}

void DetectBondStereoChemistry(ROMol &mol, const Conformer *conf) {
  PRECONDITION(conf, "no conformer");
  PRECONDITION(&(conf->getOwningMol()) == &mol,
               "conformer does not belong to molecule");
  MolOps::detectBondStereochemistry(mol, conf->getId());
}
}