-
Notifications
You must be signed in to change notification settings - Fork 0
/
astherisc.m
1355 lines (1231 loc) · 75.8 KB
/
astherisc.m
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
711
712
713
714
715
716
717
718
719
720
721
722
723
724
725
726
727
728
729
730
731
732
733
734
735
736
737
738
739
740
741
742
743
744
745
746
747
748
749
750
751
752
753
754
755
756
757
758
759
760
761
762
763
764
765
766
767
768
769
770
771
772
773
774
775
776
777
778
779
780
781
782
783
784
785
786
787
788
789
790
791
792
793
794
795
796
797
798
799
800
801
802
803
804
805
806
807
808
809
810
811
812
813
814
815
816
817
818
819
820
821
822
823
824
825
826
827
828
829
830
831
832
833
834
835
836
837
838
839
840
841
842
843
844
845
846
847
848
849
850
851
852
853
854
855
856
857
858
859
860
861
862
863
864
865
866
867
868
869
870
871
872
873
874
875
876
877
878
879
880
881
882
883
884
885
886
887
888
889
890
891
892
893
894
895
896
897
898
899
900
901
902
903
904
905
906
907
908
909
910
911
912
913
914
915
916
917
918
919
920
921
922
923
924
925
926
927
928
929
930
931
932
933
934
935
936
937
938
939
940
941
942
943
944
945
946
947
948
949
950
951
952
953
954
955
956
957
958
959
960
961
962
963
964
965
966
967
968
969
970
971
972
973
974
975
976
977
978
979
980
981
982
983
984
985
986
987
988
989
990
991
992
993
994
995
996
997
998
999
1000
function [finalReport, mdfsWithCommunity, mdfsWithoutCommunity] = astherisc(targetSubstrateReaction, targetMaxSubstrateUptake,...
minimalYieldFactor, minAbsoluteYield,...
minimalMdfAdvantage, minimalMdfWithCommunity,...
numMaxExchanges, temperature, vEpsilon,...
modelPath, reportPath, reportHeader,...
showCommunityModelBottlenecks, showSingleSpeciesBottlenecks, calculateIndirectBottlenecks,...
reactionsWithSetMinimumZero, ignoredMetabolites, fixedRatiosNameMat, exchangeReactionSelection,...
maximalMilpRunTime, verboseSettings, printValFiles, getDetailedOriginalSingleStrainSolution)
%% Algorithmic Search of THERmodynamic advantages In stoichiometric Single-species Community models
% This is the ASTHERISC package's main function astherisc. For more about ASTHERISC itself, read the "README.md" in the same folder as this script.
%
% ==ARGUMENTS==
% In order to use the astherisc function, you have to provide the following arguments in the given order:
% targetSubstrateReaction : String ~ The exchange reaction with which the target (carbon) substrate can be taken up, e.g. "R_EX_C_glc__D_exchg".
% targetMaxSubstrateUptake : Float ~ The maximal flux for the substrate uptake reaction given in targetSubstrateReaction for a single species. The negative value
% will be used as the actual lower limit.
% minimalYieldFactor : Float ~ The percentage of the maximal yield reached without community that must be reached in a community solution.
% minAbsoluteYield : Float ~ The necessary minimal absolute yield value.
% minimalMdfAdvantage : Float ~ The necessary minimal absolute optimal MDF advantage of the community solution over a single-species solution.
% minimalMdfWithCommunity : Float ~ The absolute minimal MDF value that must be reached by the solution with community.
% numMaxExchanges : Int ~ The maximal number of allowed extra exchanges, can be a fixed positive integer or inf (in the latter case, there is no
% restriction of the maximal number of allowed extra exchanges).
% temperature : Float ~ The assumed temperature in Kelvin. For reference: 25°C (77°F) equal 298.15 K,
% vEpsilon : Float ~ The minimal absolute flux value that a reaction must have in order to be considered active.
% modelPath : String ~ The (relative to CellNetAnalyzer's main folder or absolute) path to the .mat file containing the community metabolic model.
% reportPath : String ~ The (relative to CellNetAnalyzer's main folder or absolute) path to the text report of the ASTHERISC run.
% If it is "", no report file will be written (although the finalReport variable will be still generateed,.
% showCommunityModelBottlenecks : bool ~ Whether or not thermodynamic bottleneck reactions in the whole community model with its community solution shall be
% calculated and shown in the text report.
% showSingleSpeciesBottlenecks : bool ~ Whether or not thermodynamic bottleneck reactions in the single species solutions with its community solution shall be
% calculated and shown in the text report.
% calculateIndirectBottlenecks : bool ~ CURRENTLY DYSFUNCTIONAL, just set it to "false"
% reactionsWithSetMinimumZero : List[String] ~ List of reaction IDs for which the minimal alloweed flux of the associated reactions shall
% be set to zero.
% ignoredMetabolites : List[String] ~ List of metabolite IDs for which their associated metabolites a) have a fixed concentration range of [1;1] M i.e.,
% their concentrations are fixed to 1 M and b) are not unused, i.e., they are meant to have this concentration, and instead of
% "[unused]", "[1;1]" will be printed in the final text report for their metabolite concentrations.
% fixedRatiosNameMat : Matrix ~ A matrix describing enforced metabolite concentration ratio ranges of the following structure:
% [
% "$METABOLITE_ID_1" "METABOLITE_ID_2" $minimal_concentration_ratio $maximal_concentration_ratio
% ]
% exchangeReactionSelection : List[String] or [Empty] ~ If empty, all target metabolites as defined with commodepy in the model generation
% are being used. If not empty, on the the given target metabolites are used in ASTHERISC runs.
% verboseSettings: bool ~ If true, all dG'0 of the reactions as well as all metabolite concentration ranges are printed in the settings. If false,
% they will not be printed.
% printValFiles: bool ~ If true, CellNetAnalyzer .val file strings (which can be e.g. directly copied into a separate text file) will be added to the text reports for each target metabolite with a community advantage,
% including .val file strings for the single-species solution using the active community reactions as well as the community solution itself,
% in the latter case separated for each single species of the community.
% getDetailedOriginalSingleStrainSolution: bool ~ If true, the original single-strain solution (i.e., not the single-strain solution recalculated from the active community reactions)
% is printed in the results files in the form of a minimal absolute flux solution. If set in the bottleneck parameters,
% the corresponding bottlenecks are also printed.
%
% ==OUTPUTS==
% finalReport : String ~ The final text report. It will be also exported as text file to reportPath.
% mdfsWithCommunity: Vector[float] ~ The list of calculated mdfs with
% the community in cases where a community solution provides
% an MDF advantage.
% mdfsWithoutCommunity: Vector[float] ~ The list of calculated mdfs
% without the community in cases where a community solution provides
% an MDF advantage.
fullRunTime = tic; % Start measuring the time
%% Check if report path is for an existing file
if exist(reportPath, "file") == 2
disp("File "+reportPath+" already exists and will be overwritten!");
userChoice = input('Do you want to continue? Y/N [default: N]: ', 's');
if isempty(userChoice)
userChoice = 'N';
end
if userChoice ~= 'Y'
return
end
end
%% Load model
% [cnap] = TGLoadCommunityModel();
% save(modelPath, 'cnOptimal MDF with communityap');
load(modelPath, 'cnap');
cnapReactionIdsCellstring = cellstr(cnap.reacID); % Used in PSBCNAFindReactionInCellstring
%% Set up text report
finalReport = reportHeader;
finalReport = finalReport + "\n=SETTINGS=\n";
finalReport = finalReport + "Substrate reaction: " + targetSubstrateReaction + "\n";
finalReport = finalReport + "Maximal substrate uptake for single species (in units of the model): " + targetMaxSubstrateUptake + "\n";
finalReport = finalReport + "Minimal yield factor (i.e., minimal necessary percentage of maximal possible yield): " + minimalYieldFactor + "\n";
finalReport = finalReport + "Minimal absolute yield: " + minAbsoluteYield + "\n";
finalReport = finalReport + "Minimal absolute MDF community advantage: " + minimalMdfAdvantage + "\n";
finalReport = finalReport + "Temperature [K] (for comparison: 25°C=77°F=298.15 K): "+ temperature + "\n";
finalReport = finalReport + "Minimal absolute mdf with community: "+ minimalMdfWithCommunity+ "\n";
finalReport = finalReport + "Minimal absolute flux (in units of the model) for a reaction in order to be considered 'active' ('v epsilon'): " + num2str(vEpsilon) + "\n";
finalReport = finalReport + "Model path: " + modelPath + "\n";
finalReport = finalReport + "Report path: " + reportPath + "\n";
finalReport = finalReport + "Calculate and show community solution bottlenecks? " + showCommunityModelBottlenecks + "\n";
finalReport = finalReport + "Calculate and show single-species bottlenecks with active reactions of the community? " + showSingleSpeciesBottlenecks + "\n";
finalReport = finalReport + "Calculate indirect bottlenecks for selected bottleneck types? " + calculateIndirectBottlenecks + "\n";
finalReport = finalReport + "Show original single-strain solution (not the one which is recalculated from the community solution) in a verbose form? " + getDetailedOriginalSingleStrainSolution + "\n";
finalReport = finalReport + "Number of maximal allowed exchanges: " + numMaxExchanges + "\n";
finalReport = finalReport + "Reactions with set minimal flux of 0:\n";
if isempty(reactionsWithSetMinimumZero)
finalReport = finalReport + " None\n";
else
for reactionId = reactionsWithSetMinimumZero
finalReport = finalReport + " " + reactionId + "\n";
end
end
finalReport = finalReport + "'Ignored' metabolites (i.e., metabolites which are deemed to play no role thermodynamically as their concentration range is fixed to 1, so that instead of the default output '[unused]' in this case, '[1;1]' is printed instead:\n";
if isempty(ignoredMetabolites)
finalReport = finalReport + " None\n";
else
for metaboliteId = ignoredMetabolites
finalReport = finalReport + " " + metaboliteId + "\n";
end
end
finalReport = finalReport + "Fixed ratio ranges (ID of metabolite A, ID of metabolite B, minimal concentration ratio of A:B, maximal concentration ratio of A:B:\n";
if isempty(fixedRatiosNameMat)
finalReport = finalReport + " None\n";
else
for currentLine = 1:size(fixedRatiosNameMat, 1)
ratiosNameMatLine = fixedRatiosNameMat(currentLine, :);
finalReport = finalReport + " " + ratiosNameMatLine(1) + ", " + ratiosNameMatLine(2) + ", ";
finalReport = finalReport + ratiosNameMatLine(3) + ", " + ratiosNameMatLine(4) + "\n";
end
end
finalReport = finalReport + "Target exchange reaction selection:\n";
if isempty(exchangeReactionSelection)
finalReport = finalReport + " All possible ones\n";
else
for reactionId = exchangeReactionSelection
finalReport = finalReport + " " + reactionId + "\n";
end
end
%% Get species IDs
[speciesIds] = getSpeciesIdsFromCommunityModel(cnap);
%% Get all default community input and output metabolites
defaultMetabolites = [];
for i = 1:numel(cellstr(cnap.reacID))
reactionId = getIdAsString(cnap.reacID(i,:));
if ~startsWith(reactionId, "R_EX_C_")
continue
end
if (cnap.reacMin(i) ~= 0) || (cnap.reacMax(i) ~= 0)
reactionId = strrep(reactionId, "R_EX_C_", "");
reactionId = strrep(reactionId, "_exchg", "");
defaultMetabolites = [defaultMetabolites reactionId];
end
end
%% Get non-default exchange reaction IDs
[eligibleExchanges, allNondefaultExchangeReactionIndices] = getNondefaultExchangeReactionIdsFromCommunityModel(cnap, speciesIds);
%% Get all non-default community exchange reactions
[allCommunityExchangeReactions] = getAllCommunityExchangeReactionsFromCommunityModel(eligibleExchanges, speciesIds);
%% Get all potential products
if isempty(exchangeReactionSelection)
potentialProductReactions = [];
for i = 1:numel(cnap.reacMax)
reactionId = getIdAsString(cnap.reacID(i,:));
if ~startsWith(reactionId, "R_EX_C_")
continue
end
potentialProductReactions = [potentialProductReactions reactionId];
end
else
potentialProductReactions = exchangeReactionSelection;
end
%% Get general MDF MILP arguments for the given model (used for all versions of the MILP)
[RT, dG0sAndUncertainties, minConcentrationsMat, maxConcentrationsMat, fixedConcentrationRatioRanges] = getGeneralMdfMilpParameters(cnap, temperature, fixedRatiosNameMat);
if verboseSettings
finalReport = finalReport + "Set dG0 values (reaction ID, dG0):\n";
for currentReactionIndex = 1:length(dG0sAndUncertainties)
reactionId = strtrim(convertCharsToStrings(cnap.reacID(currentReactionIndex, :)));
dG0 = dG0sAndUncertainties(currentReactionIndex);
finalReport = finalReport + " " + reactionId + ", " + pCatchNanInStr(dG0) + "\n";
end
finalReport = finalReport + "Set metabolite concentrations (metabolite ID, minimal concentration, maximal concentration):\n";
for currentMetaboliteIndex = 1:length(minConcentrationsMat)
metaboliteId = strtrim(convertCharsToStrings(cnap.specID(currentMetaboliteIndex, :)));
minConcentration = minConcentrationsMat(currentMetaboliteIndex);
maxConcentration = maxConcentrationsMat(currentMetaboliteIndex);
finalReport = finalReport + " " + metaboliteId + ", " + minConcentration + ", " + maxConcentration + "\n";
end
end
finalReport = finalReport + "\n=RUN RESULTS=";
%% Set all given reaction's flux minimum to 0 (especially useful for ATPM reactions)
for reactionWithSetMinimumZero = reactionsWithSetMinimumZero
cnap.reacMin(PSBCNAFindReactionInCellstring(reactionWithSetMinimumZero, cnapReactionIdsCellstring)) = 0;
cnap.reacMin(PSBCNAFindReactionInCellstring(reactionWithSetMinimumZero, cnapReactionIdsCellstring)) = 0;
end
%% Deactivate dG0=NaN reactions except of special transporters (as identified by BiGG IDs)
cnapWithNanReactions = cnap;
counter = 1;
while counter < length(dG0sAndUncertainties)
dG0 = dG0sAndUncertainties(counter);
reactionId = convertCharsToStrings(cnap.reacID(counter, :));
if isnan(dG0)
if contains(reactionId, "tpp_") || contains(reactionId, "t1pp_") || contains(reactionId, "tex_") || endsWith(reactionId, "tex")
% tpp: Facilitated transport or (proton) symport
% t1pp: Facilitated transport or (proton) symport
% tex: "Via diffusion"
counter = counter + 1;
continue
end
if ~startsWith(reactionId, "R_EX_C_") && ~startsWith(reactionId, "R_EXCHG_")
disp(reactionId)
cnap.reacMin(counter) = 0;
cnap.reacMax(counter) = 0;
end
end
counter = counter + 1;
end
%% Perform actual MDF community benefit analysis
% -> Set up major result variables
uniqueProductsWithCommunityBenefit = [];
mdfsWithCommunity = [];
mdfsWithoutCommunity = [];
numbersOfExtraExchanges = [];
extraExchangesList = [];
forbiddenReactions = [];
mdfAdvantages = [];
maxyieldDifferencesSolutionsOnly = [];
maxyieldDifferencesAll = [];
activeExchangeCounter = zeros(1, length(cnap.reacMin));
worksWithoutNan = 0;
worksWithNan = 0;
% -> Go through each potential product
currentRound = 0; % Counter for current round
targetProductReactionIndex = 1; % find(potentialProductReactions == "R_EX_C_clpn160_exchg")+1; %%%
while targetProductReactionIndex <= length(potentialProductReactions)
targetProductReaction = potentialProductReactions(targetProductReactionIndex);
% -> Print current round and target product reaction
currentRound = currentRound + 1;
disp("Round "+num2str(currentRound)+"/"+num2str(length(potentialProductReactions))+": "+targetProductReaction);
% -> Get current target exchanges
targetExchanges = [];
targetExchangesIndices = [];
metaboliteId_part = strrep(targetProductReaction, "R_EX_C_", "");
metaboliteId = strrep(metaboliteId_part, "_exchg", "");
for j = 1:numel(speciesIds)
speciesId = speciesIds(j);
targetExchange = "R_EXCHG_"+speciesId+"_"+metaboliteId+"_p_to_"+metaboliteId;
try
PSBCNAFindReactionInCellstring(targetExchange, cnapReactionIdsCellstring);
catch
try
targetExchange = "R_EXCHG_"+speciesId+"_"+metaboliteId+"_c_to_"+metaboliteId;
PSBCNAFindReactionInCellstring(targetExchange, cnapReactionIdsCellstring);
catch
targetExchange = "R_EXCHG_"+speciesId+"_"+metaboliteId+"_to_"+metaboliteId;
end
end
targetExchanges = [targetExchanges targetExchange];
targetExchangesIndices = [targetExchangesIndices PSBCNAFindReactionInCellstring(targetExchange, cnapReactionIdsCellstring)];
end
% Starting ASTHERISC algorithm steps, with steps named as in
% ASTHERISC's publication Note that some substeps (denoted with "A"
% or "B" after the step number) may occur after some numbered steps
% (e.g. step 3B after 2A) since the numbers reflect the order logic
% as given in the publication which is different here due to the
% described usage of MDF and yield approximations which are used in
% order to reduce the computational complexity.
% -> STEP 0A: Get maximal yield for the current product with
% NaN reactions without community capability
% --> Delete any previous dYield as we use another "dYield" variable for the next MILP :D (without clear chaos would arise D:)
clear dYield
% --> Set yield function (c*r/d*r)
cYield = zeros([1, cnap.numr]);
cYield(1, PSBCNAFindReactionInCellstring(targetProductReaction, cnapReactionIdsCellstring)) = 1;
dYield = zeros([1, cnap.numr]);
dYield(1, PSBCNAFindReactionInCellstring(targetSubstrateReaction, cnapReactionIdsCellstring)) = -1; % Substrate uptake has a negative flux :O
% --> Run \o/
cnapWithNanReactionsWithoutCommunity = getCommunityModelWithSetExchanges(cnapWithNanReactions, targetSubstrateReaction, targetMaxSubstrateUptake, targetProductReaction, targetExchanges, speciesIds);
cnapWithNanReactionsWithoutCommunity = pDeactivateAllExchangesOutsideSpecies1(cnapWithNanReactionsWithoutCommunity, speciesIds);
[maxyieldWithNaNReactions, ~, success, ~] = CNAoptimizeYield(cnapWithNanReactionsWithoutCommunity,...
cYield,...
dYield,...
[],...
cnap.macroDefault,...
2);
% --> Catch potential errors
if success ~= 1
finalReport = finalReport + "\nWARNING: In NaN reactions model: No maximal yield could be calculated for "+convertCharsToStrings(targetProductReaction)+" and the model without allowed community\n";
targetProductReactionIndex = targetProductReactionIndex + 1;
continue
end
% -> STEP 0B: Get maximal yield for the current product without NaN reactions
% and without community capability
% --> Get model without community
cnapWithoutCommunity = getCommunityModelWithSetExchanges(cnap, targetSubstrateReaction, targetMaxSubstrateUptake, targetProductReaction, targetExchanges, speciesIds);
cnapWithoutCommunity = pDeactivateAllExchangesOutsideSpecies1(cnapWithoutCommunity, speciesIds);
% --> Run \o/
[maxyield, ~, success, ~] = CNAoptimizeYield(cnapWithoutCommunity,...
cYield,...
dYield,...
[],...
cnap.macroDefault,...
2);
% --> Catch potential errors
if success ~= 1
finalReport = finalReport + "\nWARNING: No maximal yield could be calculated for "+convertCharsToStrings(targetProductReaction)+" and the model without allowed community (i.e., an error occurred in CNAoptimizeYield)\n";
finalReport = finalReport + "Maxyield with NaN reactions: " + maxyieldWithNaNReactions + "\n";
targetProductReactionIndex = targetProductReactionIndex + 1;
continue
end
maxyieldDifferencesAll = [maxyieldDifferencesAll maxyieldWithNaNReactions-maxyield];
% --> Collect statistics
if (maxyieldWithNaNReactions > 0.0)
if (maxyield <= 0.0)
worksWithNan = worksWithNan + 1;
else
worksWithoutNan = worksWithoutNan + 1;
worksWithNan = worksWithNan + 1;
end
end
% --> Catch too low yield
if maxyield < minAbsoluteYield
finalReport = finalReport + "\nINFO: Maximal yield of " + maxyield + " is smaller than minimal yield for "+convertCharsToStrings(targetProductReaction)+" and the model without allowed community\n";
finalReport = finalReport + "Maxyield with NaN reactions: " + maxyieldWithNaNReactions + "\n";
targetProductReactionIndex = targetProductReactionIndex + 1;
continue
end
% -> STEP 0C: Check if the maximal production flux is high
% enough in the model without NaN reactions
cnapWithoutCommunityFBACheck = cnapWithoutCommunity;
for currentObjectiveReactionIndex = 1:length(cnap.objFunc)
cnapWithoutCommunityFBACheck.objFunc(currentObjectiveReactionIndex) = 0;
end
currentTargetIndex = PSBCNAFindReactionInCellstring(targetProductReaction, cnapReactionIdsCellstring);
cnapWithoutCommunityFBACheck.objFunc(currentTargetIndex) = -1;
[~, success, ~, optval] = CNAoptimizeFlux(cnapWithoutCommunityFBACheck, [], cnap.macroDefault, 2);
% --> Catch no success
if success ~= 1
finalReport = finalReport + "\nWARNING: No maximal product flux could be calculated for "+convertCharsToStrings(targetProductReaction)+" and the model without allowed community\n";
targetProductReactionIndex = targetProductReactionIndex + 1;
continue
end
% --> Catch too low flux
if abs(optval) < vEpsilon
finalReport = finalReport + "\nINFO: Maximal target product production reaction rate of " + optval + " is smaller than vEpsilon (set to "+vEpsilon+") for "+convertCharsToStrings(targetProductReaction)+" and the model without allowed community\n";
targetProductReactionIndex = targetProductReactionIndex + 1;
continue
end
% -> Set new yield minimum for subsequent MDF MILPs with the
% current product
targetMinYield = maxyield * minimalYieldFactor; % A bit lower in order to prevent numeric problems
% -->Set desired phenotype for OptMDFPathway-based MILPs with
% the minimal yield
numDesiredConst = 1;
D = zeros([numDesiredConst, cnap.numr]);
% Product/Substrate >= minYield <=> minYield*Substrate - Product <= 0
D(1, PSBCNAFindReactionInCellstring(targetSubstrateReaction, cnapReactionIdsCellstring)) = -targetMinYield; % Substrate uptake has a negative flux :O
D(1, PSBCNAFindReactionInCellstring(targetProductReaction, cnapReactionIdsCellstring)) = -1;
d(1) = 0;
d = d';
% -> STEP 1: Get optimal MDF without community using
% OptMDFPathway, "without community" in the definition that all
% exchange reactions are blocked.
[optmdfWithoutCommunity, vWithoutCommunity, ~, ~] = CNAcomputeOptMDFpathway_ratio_range(maximalMilpRunTime, cnapWithoutCommunity,...
RT,...
dG0sAndUncertainties,...
minConcentrationsMat,...
maxConcentrationsMat,...
D,...
d,...
fixedConcentrationRatioRanges);
% --> Catch potential NaN result
if isnan(optmdfWithoutCommunity)
finalReport = finalReport + "\nINFO: No result (probably infeasible or timeout) with OptMDFPathway and no allowed community for "+convertCharsToStrings(targetProductReaction)+"\n";
targetProductReactionIndex = targetProductReactionIndex + 1;
continue
end
reachedYieldWithoutCommunity = vWithoutCommunity(PSBCNAFindReactionInCellstring(targetProductReaction, cnapReactionIdsCellstring)) / -vWithoutCommunity(PSBCNAFindReactionInCellstring(targetSubstrateReaction, cnapReactionIdsCellstring));
% -> (Optional) STEP 1B: Get minimal flux solution with solution without community
originalSingleSpeciesBottleneckReport = "";
if getDetailedOriginalSingleStrainSolution
[optmdfMinimalFluxWithoutCommunity, vMinimalFluxWithoutCommunity, ~, dfsMinimalFluxWithoutCommunity] = CNAcomputeOptMDFpathway_higher_mdf_max_exchanges(maximalMilpRunTime, inf, [], optmdfWithoutCommunity - abs(optmdfWithoutCommunity)*.000001, true,...
cnapWithoutCommunity,...
RT,...
dG0sAndUncertainties,...
minConcentrationsMat,...
maxConcentrationsMat,...
D,...
d,...
fixedConcentrationRatioRanges);
[~, directBottlenecksStrSingle, indirectBottlenecksStrSingle, ~] = getDirectAndIndirectBottlenecks(inf, [], cnapWithoutCommunity,...
dfsMinimalFluxWithoutCommunity, RT, dG0sAndUncertainties,...
minConcentrationsMat, maxConcentrationsMat,...
D, d, fixedConcentrationRatioRanges,...
optmdfMinimalFluxWithoutCommunity, speciesIds, vMinimalFluxWithoutCommunity, vEpsilon, calculateIndirectBottlenecks,...
maximalMilpRunTime);
originalSingleSpeciesBottleneckReport = originalSingleSpeciesBottleneckReport + "Bottleneck reactions (driving force=OptMDF) of single-species solution (at maximal MDF, not recalculated from community solution reactions):\n";
originalSingleSpeciesBottleneckReport = originalSingleSpeciesBottleneckReport + "MDF in single species solution: " + optmdfMinimalFluxWithoutCommunity + "\n";
originalSingleSpeciesBottleneckReport = originalSingleSpeciesBottleneckReport + ">Bottleneck reactions (driving force=OptMDF):\n" + directBottlenecksStrSingle + "\n";
if calculateIndirectBottlenecks
originalSingleSpeciesBottleneckReport = originalSingleSpeciesBottleneckReport + ">Indirect bottleneck reactions:\n" + indirectBottlenecksStrSingle;
end
end
% -> STEP 2A:
% Check if there is a higher MDF (at least higher or equal to
% minimalMdf) with community than
% the optimal one without community using a "cut" OptMDFPathway.
% --> Get community exchange reactions
if isempty(forbiddenReactions)
usedCommunityExchangeReactions = allCommunityExchangeReactions;
else
usedCommunityExchangeReactions = allCommunityExchangeReactions(~ismember(allCommunityExchangeReactions, forbiddenReactions));
end
usedCommunityExchangeReactionsIndices = [];
for reactionCounter = 1:length(usedCommunityExchangeReactions)
currentReactionId = usedCommunityExchangeReactions(reactionCounter);
currentReactionIndex = PSBCNAFindReactionInCellstring(currentReactionId, cnapReactionIdsCellstring);
usedCommunityExchangeReactionsIndices = [usedCommunityExchangeReactionsIndices currentReactionIndex];
end
% --> Get model with community capability
cnapWithCommunityAndAllExchanges = getCommunityModelWithSetExchanges(cnap, targetSubstrateReaction, targetMaxSubstrateUptake, targetProductReaction, usedCommunityExchangeReactions, speciesIds);
% --> Run \o/
minimalMdf = optmdfWithoutCommunity + minimalMdfAdvantage;
if minimalMdf < minimalMdfWithCommunity
minimalMdf = minimalMdfWithCommunity;
end
measureMilp2Time = tic;
[mdfCommunityAndHigherMdf, vCommunityAndHigherMdf, ~, dfsCommunityAndHigherMdf] = CNAcomputeOptMDFpathway_higher_mdf_max_exchanges(maximalMilpRunTime, numMaxExchanges, allNondefaultExchangeReactionIndices, minimalMdf, false,...
cnapWithCommunityAndAllExchanges,...
RT,...
dG0sAndUncertainties,...
minConcentrationsMat,...
maxConcentrationsMat,...
D,...
d,...
fixedConcentrationRatioRanges);
timeUsed = toc(measureMilp2Time);
% --> Catch potential NaN result
if isnan(mdfCommunityAndHigherMdf)
if timeUsed >= 999.9999
finalReport = finalReport + "\nWARNING: MILP time excess with OptMDFPathway-based MILP2 and allowed community for "+convertCharsToStrings(targetProductReaction)+"\n";
else
finalReport = finalReport + "\nINFO: MILP infeasible with OptMDFPathway-based MILP2 and allowed community for "+convertCharsToStrings(targetProductReaction)+"\n";
end
finalReport = finalReport + "Reached MDF without community is " + optmdfWithoutCommunity + "\n";
targetProductReactionIndex = targetProductReactionIndex + 1;
continue
end
% --> Recheck if the MDF with community is actually higher than the one without community
% If this is not the case, proceed with the next target metabolite :O
if (mdfCommunityAndHigherMdf) <= optmdfWithoutCommunity - abs(optmdfWithoutCommunity)*.0001
finalReport = finalReport + "\nINFO: No higher MDF found with community compared to no community for "+convertCharsToStrings(targetProductReaction)+"\n";
finalReport = finalReport + "Reached MDF without community is " + optmdfWithoutCommunity + "\n";
targetProductReactionIndex = targetProductReactionIndex + 1;
continue
end
% Test for numeric problem: In the community solution, check if *both*
% species are actually used.
numberActiveReactionsPerSpecies = zeros(1, length(speciesIds));
for currentIndex = 1:length(cnap.reacMin)
if abs(vCommunityAndHigherMdf(currentIndex)) > vEpsilon
for currentSpecies = 1:length(speciesIds)
reactionIdAsStr = getIdAsString(cnap.reacID(currentIndex,:));
if endsWith(reactionIdAsStr, "_"+speciesIds(currentSpecies))
numberActiveReactionsPerSpecies(currentSpecies) = numberActiveReactionsPerSpecies(currentSpecies) + 1;
end
end
end
end
if sum(numberActiveReactionsPerSpecies == 0) == (length(numberActiveReactionsPerSpecies) - 1)
finalReport = finalReport + "\nWARNING: Numeric problem! Higher MDF found with community compared to no community even though only one species is used for "+convertCharsToStrings(targetProductReaction)+"\n";
finalReport = finalReport + "Reached MDF without community is " + optmdfWithoutCommunity + "\n";
targetProductReactionIndex = targetProductReactionIndex + 1;
pWriteReport(reportPath, finalReport);
continue
end
% -> STEP 2B: Perform optmdf approximation with the community model
% using an approximation loop
stepSizes = [1, 0.5, 0.1];
optmdfWithCommunity = NaN;
for stepSize = stepSizes
if isnan(optmdfWithCommunity)
currentMinimalMdf = optmdfWithoutCommunity;
else
currentMinimalMdf = optmdfWithCommunity;
end
while 1
currentMinimalMdf = currentMinimalMdf + stepSize;
[newOptmdfWithCommunity, newVOptMdf, ~, newDfsWithCommunity] = CNAcomputeOptMDFpathway_higher_mdf_max_exchanges(maximalMilpRunTime, numMaxExchanges, allNondefaultExchangeReactionIndices, currentMinimalMdf, false,...
cnapWithCommunityAndAllExchanges,...
RT,...
dG0sAndUncertainties,...
minConcentrationsMat,...
maxConcentrationsMat,...
D,...
d,...
fixedConcentrationRatioRanges);
if isnan(newOptmdfWithCommunity)
break
else
optmdfWithCommunity = newOptmdfWithCommunity;
mdfConstraint = optmdfWithCommunity;
vOptMdf = newVOptMdf;
dfsOptMdf = newDfsWithCommunity;
end
end
end
% --> Catch numeric problem
if (optmdfWithCommunity < minimalMdf - 0.0001)
finalReport = finalReport + "\nWARNING: Numeric problem (community OptMDF is lower than single species OptMDF, still MILP2 works) for "+convertCharsToStrings(targetProductReaction)+"\n";
targetProductReactionIndex = targetProductReactionIndex + 1;
continue
end
% --> Catch NaN
if isnan(optmdfWithCommunity)
errorOptMdfCommunity = true;
vOptMdf = vCommunityAndHigherMdf;
dfsOptMdf = dfsCommunityAndHigherMdf;
mdfConstraint = mdfCommunityAndHigherMdf - 0.00001;
optmdfWithCommunity = mdfCommunityAndHigherMdf - 0.00001;
else
errorOptMdfCommunity = false;
end
% -> Check for further numeric problems in solution (sometimes,
% reactions with a *very* low flux occur, even though they are
% shown with a flux of "0" in the resulting OptMDFPathway flux
% vector D:)
cnapTest = cnapWithCommunityAndAllExchanges;
dG0sAndUncertaintiesTest = dG0sAndUncertainties;
for i = 1:length(cnap.reacMin)
if vOptMdf(i) == 0
cnapTest.reacMin(i) = 0;
cnapTest.reacMax(i) = 0;
end
end
[optmdfWithCommunityTest, ~, ~, ~] = CNAcomputeOptMDFpathway_ratio_range_max_exchanges(maximalMilpRunTime, numMaxExchanges, allNondefaultExchangeReactionIndices, cnapTest,...
RT,...
dG0sAndUncertaintiesTest,...
minConcentrationsMat,...
maxConcentrationsMat,...
D,...
d,...
fixedConcentrationRatioRanges);
if (optmdfWithCommunityTest) - abs(optmdfWithCommunityTest)*.000001 <= optmdfWithoutCommunity
finalReport = finalReport + "\nINFO: Numeric problem! Higher MDF found with community compared to no community cannot be reproduced for "+convertCharsToStrings(targetProductReaction)+"\n";
targetProductReactionIndex = targetProductReactionIndex + 1;
pWriteReport(reportPath, finalReport);
continue
end
% -> STEP 3A: Perform yield optimization at the maximal
% community MDF
stepSizes = [0.5, 0.1, 0.05, 0.01];
maxyieldCommunityAtOptmdf = NaN;
for stepSize = stepSizes
if isnan(maxyieldCommunityAtOptmdf)
currentMinimalYield = targetMinYield;
else
currentMinimalYield = maxyieldCommunityAtOptmdf;
end
while 1
currentMinimalYield = currentMinimalYield + stepSize;
% -->Set desired phenotype for OptMDFPathway-based MILPs with
% the minimal yield
D_maxyield = zeros([1, cnap.numr]);
% Product/Substrate >= minYield <=> minYield*Substrate - Product <= 0
D_maxyield(1, PSBCNAFindReactionInCellstring(targetSubstrateReaction, cnapReactionIdsCellstring)) = -currentMinimalYield; % Substrate uptake has a negative flux :O
D_maxyield(1, PSBCNAFindReactionInCellstring(targetProductReaction, cnapReactionIdsCellstring)) = -1;
d_maxyield(1) = 0;
d_maxyield = d_maxyield';
[newOptmdfWithCommunity, newVOptMdf, ~, newDfsWithCommunity] = CNAcomputeOptMDFpathway_higher_mdf_max_exchanges(maximalMilpRunTime, numMaxExchanges, allNondefaultExchangeReactionIndices, mdfConstraint, false,...
cnapWithCommunityAndAllExchanges,...
RT,...
dG0sAndUncertainties,...
minConcentrationsMat,...
maxConcentrationsMat,...
D_maxyield,...
d_maxyield,...
fixedConcentrationRatioRanges);
if isnan(newOptmdfWithCommunity)
break
else
optmdfWithCommunity = newOptmdfWithCommunity;
mdfConstraint = newOptmdfWithCommunity;
vOptMdf = newVOptMdf;
dfsOptMdf = newDfsWithCommunity;
maxyieldCommunityAtOptmdf = currentMinimalYield;
end
end
end
% -->Set desired phenotype for OptMDFPathway-based MILPs with
% the maximal yield at the maximal MDF
if isnan(maxyieldCommunityAtOptmdf)
errorApproximatedYield = true;
maxyieldCommunityAtOptmdf = targetMinYield;
else
errorApproximatedYield = false;
end
D = zeros([1, cnap.numr]);
% Product/Substrate >= minYield <=> minYield*Substrate - Product <= 0
D(1, PSBCNAFindReactionInCellstring(targetSubstrateReaction, cnapReactionIdsCellstring)) = -maxyieldCommunityAtOptmdf; % Substrate uptake has a negative flux :O
D(1, PSBCNAFindReactionInCellstring(targetProductReaction, cnapReactionIdsCellstring)) = -1;
d(1) = 0;
d = d';
% -> STEP 2C: Calculate exact optimal MDF at the approximated optimal yield
cnapWithMaxyieldMaxmdfReactionsOnly = pGetCnapWithBlockedReactionsWhereVIsZero(cnapWithCommunityAndAllExchanges, vOptMdf, vEpsilon);
[mdfWithMaxyieldMaxmdf, vWithMaxyieldMaxmdf, ~, dfsWithMaxyieldMaxmdf] = CNAcomputeOptMDFpathway_ratio_range_max_exchanges(maximalMilpRunTime, numMaxExchanges, allNondefaultExchangeReactionIndices,...
cnapWithMaxyieldMaxmdfReactionsOnly,...
RT,...
dG0sAndUncertainties,...
minConcentrationsMat,...
maxConcentrationsMat,...
D,...
d,...
fixedConcentrationRatioRanges);
if ~isnan(mdfWithMaxyieldMaxmdf)
optmdfWithCommunity = mdfWithMaxyieldMaxmdf - 0.0001;
mdfConstraint = mdfWithMaxyieldMaxmdf - 0.0001;
vOptMdf = vWithMaxyieldMaxmdf;
dfsOptMdf = dfsWithMaxyieldMaxmdf;
exactCommunityMdfCalculationError = false;
mdfAdvantage = mdfConstraint - optmdfWithoutCommunity;
mdfAdvantages = [mdfAdvantages mdfAdvantage];
else
exactCommunityMdfCalculationError = true;
end
% -> STEP 4: Get mdf solution with minimal flux at maximal
% community MDF & yield at this MDF
cnapWithCommunityAndMinimalFluxReactionsOnly = pGetCnapWithBlockedReactionsWhereVIsZero(cnapWithCommunityAndAllExchanges, vOptMdf, vEpsilon);
if ~errorOptMdfCommunity
[mdfMinimalFlux, vMinimalFlux, ~, dfsMinimalFlux] = CNAcomputeOptMDFpathway_higher_mdf_max_exchanges(maximalMilpRunTime, numMaxExchanges, allNondefaultExchangeReactionIndices, mdfConstraint - abs(mdfConstraint)*.000001, true,...
cnapWithCommunityAndMinimalFluxReactionsOnly,...
RT,...
dG0sAndUncertainties,...
minConcentrationsMat,...
maxConcentrationsMat,...
D,...
d,...
fixedConcentrationRatioRanges);
% Catch NaN
if isnan(mdfMinimalFlux)
errorOptMdfMinimalFlux = true;
else
errorOptMdfMinimalFlux = false;
vOptMdf = vMinimalFlux;
dfsOptMdf = dfsMinimalFlux;
end
else
errorOptMdfMinimalFlux = true;
end
% --> STEP 3B: Calculate exact maximal yield for text report
cnapWithCommunityAndMinimalFluxReactions = pGetCnapWithBlockedReactionsWhereVIsZero(cnapWithCommunityAndMinimalFluxReactionsOnly, vOptMdf, vEpsilon);
% --> Set yield function (c*r/d*r) and get optimal yield with minimal active reactions
[reachedYield, ~, success, ~] = CNAoptimizeYield(cnapWithCommunityAndMinimalFluxReactions,...
cYield,...
dYield,...
[],...
cnap.macroDefault,...
2);
% --> Catch potential errors
if success ~= 1
errorMaximalCommunityYield = true;
reachedYield = -vOptMdf(PSBCNAFindReactionInCellstring(targetProductReaction, cnapReactionIdsCellstring)) / vOptMdf(PSBCNAFindReactionInCellstring(targetSubstrateReaction, cnapReactionIdsCellstring));
else
errorMaximalCommunityYield = false;
end
% --> Get number of reactions and total flux for each species
% with the minimal total flux solution
substrateUptakeRate = vOptMdf(PSBCNAFindReactionInCellstring(targetSubstrateReaction, cnapReactionIdsCellstring));
fluxScaleVector = abs(targetMaxSubstrateUptake / substrateUptakeRate);
numberSpecies = length(speciesIds);
numberReactionsPerSpecies = zeros(numberSpecies, 1);
totalFluxPerSpecies = zeros(numberSpecies, 1);
currentReactionIndex = 1;
while currentReactionIndex < length(vOptMdf)
vSelection = vOptMdf(currentReactionIndex);
if abs(vSelection) < vEpsilon
currentReactionIndex = currentReactionIndex + 1;
continue
end
current_reactionId = getIdAsString(cnap.reacID(currentReactionIndex, :));
currentSpeciesIndex = 1;
for speciesId = speciesIds
if ~endsWith(current_reactionId, speciesId)
currentSpeciesIndex = currentSpeciesIndex + 1;
continue
end
numberReactionsPerSpecies(currentSpeciesIndex) = numberReactionsPerSpecies(currentSpeciesIndex) + 1;
totalFluxPerSpecies(currentSpeciesIndex) = totalFluxPerSpecies(currentSpeciesIndex) + abs(vSelection);
currentSpeciesIndex = currentSpeciesIndex + 1;
end
currentReactionIndex = currentReactionIndex + 1;
end
speciesSpecificReactionReport = "";
currentSpeciesIndex = 1;
for speciesId = speciesIds
numberReactions = numberReactionsPerSpecies(currentSpeciesIndex);
total_flux = totalFluxPerSpecies(currentSpeciesIndex) * fluxScaleVector;
speciesSpecificReactionReport = speciesSpecificReactionReport + speciesId + ": " + num2str(numberReactions) + " | " + num2str(total_flux) + "\n";
currentSpeciesIndex = currentSpeciesIndex + 1;
end
% -> STEP 5: Get active metabolite concentration ranges
% Based on (heavily modified) code provided by Axel von Kamp :-)
% --> Get active metabolites (i.e., metabolites which occur in
% reactions that are active in the OptMDFPathway solution)
activeMetaboliteIndices = find(any(cnapWithCommunityAndMinimalFluxReactions.stoichMat(:, (abs(vOptMdf)>vEpsilon)), 2));
% --> Get concentration range vectors
[cMins, cMaxs, activeMetaboliteIndices, errorConcentrationRanges] = getConcentrationRanges(numMaxExchanges, allNondefaultExchangeReactionIndices, mdfConstraint,...
cnapWithCommunityAndMinimalFluxReactions,...
D, d,...
dG0sAndUncertainties,...
RT,...
minConcentrationsMat,...
maxConcentrationsMat,...
fixedConcentrationRatioRanges,...
activeMetaboliteIndices,...
maximalMilpRunTime);
% --> Find non-overlapping metabolite concentration ranges
occuringMetabolitesStr = "";
nonOccuringMetabolitesStr = "";
analyzedMetaboliteIndices = [];
for metaboliteIndex = 1:length(cMins)
% Check if there is a metabolite range with NaN
currentCMin = cMins(metaboliteIndex);
currentCMax = cMaxs(metaboliteIndex);
% Ignore if cMin and cMax are equal to 0
if isnan(currentCMin) || isnan(currentCMax)
continue
end
% Ignore if metabolite is already analyzed
if ismember(metaboliteIndex, analyzedMetaboliteIndices)
continue
end
% Get the metabolite's ID
try
baseMetaboliteId = cnap.specID(metaboliteIndex,:);
catch
disp("A")
end
baseMetaboliteId = getIdAsString(baseMetaboliteId);
baseMetaboliteSpecies = pGetSpeciesFromId(baseMetaboliteId);
% Catch exchanges
if ~ismember(baseMetaboliteSpecies, speciesIds)
continue
end
% Get metabolite index in all species
metaboliteIndexInAllSpecies = [];
metaboliteIdInAllSpecies = [];
for speciesId = speciesIds
speciesMetaboliteId = strrep(baseMetaboliteId, "_"+baseMetaboliteSpecies, "_"+speciesId);
species_metaboliteIndex = PSBCNAFindMetabolite(speciesMetaboliteId, cnap);
metaboliteIndexInAllSpecies = [metaboliteIndexInAllSpecies species_metaboliteIndex];
metaboliteIdInAllSpecies = [metaboliteIdInAllSpecies speciesMetaboliteId];
end
% Check if the metabolite ranges are overlapping
firstIndex = metaboliteIndexInAllSpecies(1);
selectionCMin = cMins(firstIndex);
selectionCMax = cMaxs(firstIndex);
foundNan = false;
for unused_counter_xD = 1:length(metaboliteIndexInAllSpecies)
for currentSpecies = 1:length(metaboliteIndexInAllSpecies)
currentMetaboliteIndexInSpecies = metaboliteIndexInAllSpecies(currentSpecies);
currentCMin = cMins(currentMetaboliteIndexInSpecies);
currentCMax = cMaxs(currentMetaboliteIndexInSpecies);
if isnan(currentCMin) || isnan(currentCMax)
foundNan = true;
end
% Extension below
if (currentCMin < selectionCMin) && (currentCMax >= selectionCMin)
selectionCMin = currentCMin;
end
% Extension above
if (currentCMax > selectionCMax) && (currentCMin <= selectionCMax)
selectionCMax = currentCMax;
end
end
end
speciesWideMetaboliteCMin = min(cMins(metaboliteIndexInAllSpecies));
speciesWideMetaboliteCMax = max(cMaxs(metaboliteIndexInAllSpecies));
% Catch metabolites which are not active in all species
if foundNan
continue
end
% Add metabolite with its concentration range if it is
% non-overlapping to text report
if (selectionCMin ~= speciesWideMetaboliteCMin) || (selectionCMax ~= speciesWideMetaboliteCMax)
speciesReport = "";
foundNaN = false;
for currentSpecies = 1:length(metaboliteIndexInAllSpecies)
metaboliteIndex = metaboliteIndexInAllSpecies(currentSpecies);
metaboliteId = metaboliteIdInAllSpecies(currentSpecies);
currentCMin = exp(cMins(metaboliteIndex));
currentCMax = exp(cMaxs(metaboliteIndex));
currentCMinAsStr = num2str(currentCMin);
currentCMaxAsStr = num2str(currentCMax);
if (currentCMin == currentCMax == 1)
foundNan = true;
end
speciesReport = speciesReport + metaboliteId + " " + pAddConcentrationString(currentCMinAsStr, currentCMaxAsStr, metaboliteId, ignoredMetabolites) + " & ";
end
if foundNan
nonOccuringMetabolitesStr = nonOccuringMetabolitesStr + speciesReport + "X";
else
occuringMetabolitesStr = occuringMetabolitesStr + speciesReport + "X";
end
end
analyzedMetaboliteIndices = [analyzedMetaboliteIndices metaboliteIndexInAllSpecies];
end
numOverlappingMetabolitesStr = occuringMetabolitesStr + nonOccuringMetabolitesStr;
% Post-process output string of non-overlapping metabolite
% concentration ranges
numOverlappingMetabolitesStr = strrep(numOverlappingMetabolitesStr, " & X", "\n");
if numOverlappingMetabolitesStr == "X"
numOverlappingMetabolitesStr = "";
end
%%%%
% --> Get all non-default active exchanges from the solution with
% community and minimal extra exchanges (5th main step) as a list of strings containing the
% exchange IDs
activeExchanges = cnap.reacID(abs(vOptMdf)>vEpsilon, :);
activeExchangesAsStrList = [];
activeExchangesIndices = [];
for j = 1:length(cellstr(activeExchanges))
reactionId = getIdAsString(activeExchanges(j,:));
if ~startsWith(reactionId, "R_EXCHG_")
continue
end
reactionIdSplit = strsplit(reactionId, "_to_");
metaboliteId = reactionIdSplit(2);
if ismember(metaboliteId, defaultMetabolites)
continue
end
index = PSBCNAFindReactionInCellstring(reactionId, cnapReactionIdsCellstring);
activeExchangeCounter(index) = activeExchangeCounter(index) + 1;
activeExchangesIndices = [activeExchangesIndices index];
activeExchangesAsStrList = [activeExchangesAsStrList reactionId];
end
numberOfExtraExchanges = length(activeExchangesAsStrList);
% --> Get extra exchanges and default exchanges output string
extraExchangesAsStr = "";
extraExchangesAsVector = [];
defaultExchangesAsStr = "";
for j = 1:length(cellstr(activeExchanges))
reactionId = getIdAsString(activeExchanges(j,:));
if ~startsWith(reactionId, "R_EXCHG_")
continue
end
reactionIdSplit = strsplit(reactionId, "_to_");
metaboliteId = reactionIdSplit(2);
reactionIndex = PSBCNAFindReactionInCellstring(reactionId, cnapReactionIdsCellstring);
scaledFlux = fluxScaleVector * vOptMdf(reactionIndex);
if abs(scaledFlux) < vEpsilon
continue
end
exchangeReportAsStr = reactionId + " | SCALED FLUX: " + num2str(scaledFlux);
% Get exchange report after identifying the exchange's
% metabolites
reaction_row = cnap.stoichMat(:, reactionIndex);
metabolite_indices = find(reaction_row ~= 0);
for metaboliteIndex = metabolite_indices'
metaboliteId = getIdAsString(cnap.specID(metaboliteIndex,:));
metaboliteCRangeAsStr = pAddConcentrationString(exp(cMins(metaboliteIndex)), exp(cMaxs(metaboliteIndex)), metaboliteId, ignoredMetabolites);
exchangeReportAsStr = exchangeReportAsStr + " | " + metaboliteId + " " + metaboliteCRangeAsStr;
end
exchangeReportAsStr = exchangeReportAsStr + "\n";
rawMetaboliteId = strrep("X"+metaboliteId, "XM_", "");
rawMetaboliteId = strrep(rawMetaboliteId+"X", "_exchgX", "");
if ismember(rawMetaboliteId, defaultMetabolites)
disp("DEFAULT")
disp(metaboliteId)
defaultExchangesAsStr = defaultExchangesAsStr + exchangeReportAsStr;
else
disp("NON-DEFAULT")
disp(metaboliteId)
extraExchangesAsStr = extraExchangesAsStr + exchangeReportAsStr;
extraExchangesAsVector = [extraExchangesAsVector reactionId];
end
end
% -> STEP 6A: Get active species and calculate bottlenecks
% with the single-species solutions for active species in the
% community-free solution with the minimal absolute flux sum
% Get bottlenecks of each active species
singleSpeciesBottlenecksStr = "";
hasNumericError = false;
if showSingleSpeciesBottlenecks
for currentSpecies = speciesIds(1) % Should be changed for multi-species communities
cnapWithOneSpeciesOnly = pGetCnapWithActiveReactionsInBothSpecies(cnapWithCommunityAndAllExchanges, vOptMdf, speciesIds, vEpsilon);
cnapWithOneSpeciesOnly = getCommunityModelWithSetExchanges(cnapWithOneSpeciesOnly, targetSubstrateReaction, targetMaxSubstrateUptake, targetProductReaction, targetExchanges, speciesIds);
cnapWithOneSpeciesOnly = pDeactivateAllExchangesOutsideSpecies1(cnapWithOneSpeciesOnly, speciesIds);
for currentReactionIndex = 1:length(cnapWithOneSpeciesOnly.reacMin)
current_reactionId = getIdAsString(cnapWithOneSpeciesOnly.reacID(currentReactionIndex,:));
if ~startsWith(current_reactionId, "R_EXCHG_")
continue
end
if ~startsWith(current_reactionId, "R_EXCHG_"+currentSpecies+"_")
cnapWithOneSpeciesOnly.reacMin(currentReactionIndex) = 0;
cnapWithOneSpeciesOnly.reacMax(currentReactionIndex) = 0;
end
end
[mdfWithSingleSpecies, vWithSingleSpecies, ~, dfsWithSingleSpecies] = CNAcomputeOptMDFpathway_ratio_range_max_exchanges(maximalMilpRunTime, numMaxExchanges, allNondefaultExchangeReactionIndices, cnapWithOneSpeciesOnly,...
RT,...
dG0sAndUncertainties,...
minConcentrationsMat,...
maxConcentrationsMat,...
D,...
d,...
fixedConcentrationRatioRanges);
if isnan(mdfWithSingleSpecies)
vWithSingleSpecies = [];
continue
end
if (mdfWithSingleSpecies-0.001) > optmdfWithoutCommunity
finalReport = finalReport + "WARNING: Inconsistent single-species solution for " + targetProductReaction + "! This is probably caused by a numeric problem\n";
end
cnapWithOneSpeciesOnlyAndActiveReactionsOnly = pGetCnapWithBlockedReactionsWhereVIsZero(cnapWithOneSpeciesOnly, vWithSingleSpecies, vEpsilon);
[~, directBottlenecksStr, indirectBottlenecksStr, connectionMetaboliteIndices] = getDirectAndIndirectBottlenecks(numMaxExchanges, allNondefaultExchangeReactionIndices, cnapWithOneSpeciesOnlyAndActiveReactionsOnly,...
dfsWithSingleSpecies, RT, dG0sAndUncertainties,...
minConcentrationsMat, maxConcentrationsMat,...
D, d, fixedConcentrationRatioRanges,...
mdfWithSingleSpecies, speciesIds, vWithSingleSpecies, vEpsilon, calculateIndirectBottlenecks,...
maximalMilpRunTime);
[cMinsSingleSpecies, cMaxsSingleSpecies, ~, ~] = getConcentrationRanges(numMaxExchanges, allNondefaultExchangeReactionIndices, mdfWithSingleSpecies,...
cnapWithOneSpeciesOnlyAndActiveReactionsOnly,...
D, d,...
dG0sAndUncertainties,...
RT,...
minConcentrationsMat, maxConcentrationsMat,...