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ifold.cc
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/******************************************************************************
* Copyright (C) 2014 Juan Antonio Garcia Martin , Peter Clote, Ivan Dotu *
* *
* This program is free software: you can redistribute it and/or modify *
* it under the terms of the GNU General Public License as published by *
* the Free Software Foundation, either version 3 of the License, or *
* (at your option) any later version. *
* *
* This program 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 General Public License for more details. *
* *
* You should have received a copy of the GNU General Public License *
* along with this program. If not, see <http://www.gnu.org/licenses/>. *
******************************************************************************/
#include <stdio.h>
#include <string.h>
#include <stdlib.h>
#include <math.h>
#include <limits.h>
#include "energy_constant.h"
#include "vienna_constraint.h"
#include "minenergy_constraint.h"
#include "minensdef_constraint.h"
#include "energy_constraint.h"
#include "ensdef_constraint.h"
#include "restart_monitor.h"
#include "ifold.h"
#include "diversity_measures.h"
using namespace std;
namespace operations_research {
IFold::~IFold(){};
IFold::IFold(Solver* const _solver,int _n) :
solver(_solver),n(_n){
vSeq = vector<IntVar *> (n+1);
vSeqGolomb = vector<IntVar *> (n+1);
dangles_=1;
energyModel_=getExecPath("");
energyModel_.append("/");
energyModel_.append(TURNER_04_FILE);
rnaLib_ = VIENNA_LIB;
}
IFold::IFold(Solver* const _solver,int _n, int dangles, std::string rnaLib, std::string energyModel) :
solver(_solver),n(_n), dangles_(dangles), rnaLib_(rnaLib), energyModel_(energyModel){
vSeq = vector<IntVar *> (n+1);
vSeqGolomb = vector<IntVar *> (n+1);
}
void IFold::InitSequenceDomain(char* sequence){
int i;
IUPAC['N'] = vector<int> {2,0,1,3}; //All
IUPAC['A'] = vector<int> {0}; //A
IUPAC['C'] = vector<int> {1}; //C
IUPAC['G'] = vector<int> {2}; //G
IUPAC['U'] = vector<int> {3}; //T
IUPAC['V'] = vector<int> {2,0,1}; //G,A,C
IUPAC['B'] = vector<int> {2,3,1}; //G,U,C
IUPAC['H'] = vector<int> {0,3,1}; //A,U,C
IUPAC['D'] = vector<int> {2,0,3}; //G,A,U
IUPAC['K'] = vector<int> {2,3}; //G,U
IUPAC['S'] = vector<int> {2,1}; //G,C
IUPAC['W'] = vector<int> {0,3}; //A,U
IUPAC['M'] = vector<int> {0,1};//A,C
IUPAC['Y'] = vector<int> {1,3}; //C,T
IUPAC['R'] = vector<int> {0,2}; //A,G
if(strlen(sequence) == 0){
for(i = 0; i < n; i++){
sequence[i] = 'N';
}
}
sequence[n] = '\0';
vSeq[0] = solver->MakeIntConst(-1);
vSeqGolomb[0] = solver->MakeIntConst(-1);
for(i = 1; i <= n; i++){
vSeq[i] = solver->MakeIntVar(IUPAC[sequence[i-1]], absl::StrFormat("S_%03d", i));
vSeqGolomb[i] =solver->MakeElement(golomb,vSeq[i])->Var();
}
}
void IFold::InitDomains(char* sequence){
InitSequenceDomain(sequence);
}
void IFold::AddAminoAcidConstraint(AAConstraint* aaConstraint){
int nCodons= aaConstraint->getLength();
if(nCodons>0){
codonPositions.push_back(std::make_pair(aaConstraint->getStartPos(),nCodons));
IntVar* const12 = solver->MakeIntConst(12);
int currentCodons=vCodons.size();
for(int i=0;i<nCodons;i++){
vCodons.push_back(solver->MakeIntVar(aaConstraint->getDomain(i), absl::StrFormat("AA_%03d", i+currentCodons)));
// Constraint to transform nucleotides sequence to codons ((vSeq[i*3]-vSeq[(i*3)+1] + ((vSeq[i*3]==vSeq[(i*3)+1])*vSeq[i*3]) + 12)+(vSeq[(i*3)+2] * 25))
IntVar* equalSecondFirst = solver->MakeIsEqualVar(vSeqGolomb[(i*3)+aaConstraint->getStartPos()],vSeqGolomb[((i*3)+1)+aaConstraint->getStartPos()]);
solver->AddConstraint(solver->MakeEquality(vCodons[currentCodons+i],
solver->MakeSum(
solver->MakeSum(
solver->MakeDifference(vSeqGolomb[(i*3)+aaConstraint->getStartPos()],vSeqGolomb[((i*3)+1)+aaConstraint->getStartPos()])->Var(),
solver->MakeSum(solver->MakeProd(equalSecondFirst,vSeqGolomb[(i*3)+aaConstraint->getStartPos()])->Var(),const12)->Var())->Var(),
solver->MakeProd(vSeqGolomb[((i*3)+2)+aaConstraint->getStartPos()],25)->Var())->Var()
));
// Contraints for BLOSUM score maximization
if(aaConstraint->maximizeScore() && aaConstraint->getTarget().length() > 0){
maxBlosumValue+=aaConstraint->getMaxBlosumValue(i);
vAaSeqSimilarity.push_back(solver->MakeElement(aaBlosum[aaConstraint->getBlosumIndex(i)],vCodons[currentCodons+i])->Var());
}
}
}
}
void IFold::AddNucleotideRangeConstraints(double minGCcont, double maxGCcont, int minAU, int maxAU, int minGC, int maxGC, int minGU, int maxGU,std::vector<std::tuple<int,int,int>> listMinA,std::vector<std::tuple<int,int,int>> listMaxA,std::vector<std::tuple<int,int,int>> listMinC,std::vector<std::tuple<int,int,int>> listMaxC,std::vector<std::tuple<int,int,int>> listMinG,std::vector<std::tuple<int,int,int>> listMaxG,std::vector<std::tuple<int,int,int>> listMinU,std::vector<std::tuple<int,int,int>> listMaxU,std::vector<std::tuple<int,int,int>> listConsA,std::vector<std::tuple<int,int,int>> listConsC,std::vector<std::tuple<int,int,int>> listConsG,std::vector<std::tuple<int,int,int>> listConsU){
int i,j;
// GC content contraints
int intMinGCcont = (minGCcont == 0) ? 0 : (int) ceil((n*minGCcont)/100.0);
int intMaxGCcont = (maxGCcont == 100) ? n : (int) floor((n*maxGCcont)/100.0);
if(intMinGCcont>0 || intMaxGCcont < n){
vector<IntVar*> gcCont = vector<IntVar *> (n);
for(i = 1; i <= n; i++){
gcCont[i-1] = solver->MakeElement(isGC,vSeq[i])->Var();
}
solver->AddConstraint(solver->MakeBetweenCt(solver->MakeSum(gcCont)->Var(),intMinGCcont,intMaxGCcont));
}
// Contraints for number of base pairs of each type (applicable to all target structures)
for(j=0;j<vBPs.size();j++){
int intMinAU = (minAU == 0) ? 0 : minAU;
int intMaxAU = (maxAU == -1) ? vBPs.at(j).size(): maxAU;
if(intMinAU > 0 || intMaxAU < vBPs.at(j).size()){
vector<IntVar*> numAU = vector<IntVar *> (vBPs.at(j).size());
for(i = 0; i <vBPs.at(j).size() ; i++){
numAU[i] = solver->MakeIsEqualCstVar(solver->MakeAbs(vBPs.at(j)[i]),9);
}
solver->AddConstraint(solver->MakeBetweenCt(solver->MakeSum(numAU)->Var(),intMinAU,intMaxAU));
}
int intMinGC = (minGC == 0) ? 0 : minGC;
int intMaxGC = (maxGC == -1) ? vBPs.at(j).size(): maxGC;
if(intMinGC > 0 || intMaxGC < vBPs.at(j).size()){
vector<IntVar*> numGC = vector<IntVar *> (vBPs.at(j).size());
for(i = 0; i <vBPs.at(j).size() ; i++){
numGC[i] = solver->MakeIsEqualCstVar(solver->MakeAbs(vBPs.at(j)[i]),6);
}
solver->AddConstraint(solver->MakeBetweenCt(solver->MakeSum(numGC)->Var(),intMinGC,intMaxGC));
}
int intMinGU = (minGU == 0) ? 0 : minGU;
int intMaxGU = (maxGU == -1) ? vBPs.at(j).size(): maxGU;
if(intMinGU > 0 || intMaxGU < vBPs.at(j).size()){
vector<IntVar*> numGU = vector<IntVar *> (vBPs.at(j).size());
for(i = 0; i <vBPs.at(j).size() ; i++){
numGU[i] = solver->MakeIsEqualCstVar(solver->MakeAbs(vBPs.at(j)[i]),11);
}
solver->AddConstraint(solver->MakeBetweenCt(solver->MakeSum(numGU)->Var(),intMinGU,intMaxGU));
}
}
// Constraints for maximum and minimum nucleotides
if(listMinA.size()>0 || listMaxA.size()>0){
vector<IntVar*> numA = vector<IntVar *> (n);
for(i = 1; i<=n ; i++){
numA[i-1] = solver->MakeIsEqualCstVar(vSeq[i],0);
}
for(j=0;j<listMinA.size();j++){
solver->AddConstraint(solver->MakeGreaterOrEqual(solver->MakeSum(std::vector<IntVar*>(numA.begin () + get<1>(listMinA[j])-1, numA.begin()+ get<2>(listMinA[j])))->Var(), get<0>(listMinA[j])));
}
for(j=0;j<listMaxA.size();j++){
solver->AddConstraint(solver->MakeLessOrEqual(solver->MakeSum(std::vector<IntVar*>(numA.begin () + get<1>(listMaxA[j])-1, numA.begin()+ get<2>(listMaxA[j])))->Var(), get<0>(listMaxA[j])));
}
}
if(listMinC.size()>0 || listMaxC.size()>0){
vector<IntVar*> numC = vector<IntVar *> (n);
for(i = 1; i<=n ; i++){
numC[i-1] = solver->MakeIsEqualCstVar(vSeq[i],1);
}
for(j=0;j<listMinC.size();j++){
solver->AddConstraint(solver->MakeGreaterOrEqual(solver->MakeSum(std::vector<IntVar*>(numC.begin () + get<1>(listMinC[j])-1, numC.begin()+ get<2>(listMinC[j])))->Var(), get<0>(listMinC[j])));
}
for(j=0;j<listMaxC.size();j++){
solver->AddConstraint(solver->MakeLessOrEqual(solver->MakeSum(std::vector<IntVar*>(numC.begin () + get<1>(listMaxC[j])-1, numC.begin()+ get<2>(listMaxC[j])))->Var(), get<0>(listMaxC[j])));
}
}
if(listMinG.size()>0 || listMaxG.size()>0){
vector<IntVar*> numG = vector<IntVar *> (n);
for(i = 1; i<=n ; i++){
numG[i-1] = solver->MakeIsEqualCstVar(vSeq[i],2);
}
for(j=0;j<listMinG.size();j++){
solver->AddConstraint(solver->MakeGreaterOrEqual(solver->MakeSum(std::vector<IntVar*>(numG.begin () + get<1>(listMinG[j])-1, numG.begin()+ get<2>(listMinG[j])))->Var(), get<0>(listMinG[j])));
}
for(j=0;j<listMaxG.size();j++){
solver->AddConstraint(solver->MakeLessOrEqual(solver->MakeSum(std::vector<IntVar*>(numG.begin () + get<1>(listMaxG[j])-1, numG.begin()+ get<2>(listMaxG[j])))->Var(), get<0>(listMaxG[j])));
}
}
if(listMinU.size()>0 || listMaxU.size()>0){
vector<IntVar*> numU = vector<IntVar *> (n);
for(i = 1; i<=n ; i++){
numU[i-1] = solver->MakeIsEqualCstVar(vSeq[i],3);
}
for(j=0;j<listMinU.size();j++){
solver->AddConstraint(solver->MakeGreaterOrEqual(solver->MakeSum(std::vector<IntVar*>(numU.begin () + get<1>(listMinU[j])-1, numU.begin()+ get<2>(listMinU[j])))->Var(), get<0>(listMinU[j])));
}
for(j=0;j<listMaxU.size();j++){
solver->AddConstraint(solver->MakeLessOrEqual(solver->MakeSum(std::vector<IntVar*>(numU.begin () + get<1>(listMaxU[j])-1, numU.begin()+ get<2>(listMaxU[j])))->Var(), get<0>(listMaxU[j])));
}
}
// Constraints for maximum consecutive nucleotides
if(listConsA.size() > 0){
vector<IntVar*> vNoA = vector<IntVar *> (n);
for(i = 1; i <= n; i++){
vNoA[i-1] = solver->MakeIsDifferentCstVar(vSeq[i],0);
}
for(j=0;j<listConsA.size();j++){
for(i=(get<1>(listConsA[j]))-1;i<get<2>(listConsA[j])-get<0>(listConsA[j])-1;i++){
solver->AddConstraint(solver->MakeGreaterOrEqual(solver->MakeSum(std::vector<IntVar*>(vNoA.begin () + i, vNoA.begin()+ i+get<0>(listConsA[j])+1))->Var(),1));
}
}
}
if(listConsC.size() > 0){
vector<IntVar*> vNoC = vector<IntVar *> (n);
for(i = 1; i <= n; i++){
vNoC[i-1] = solver->MakeIsDifferentCstVar(vSeq[i],1);
}
for(j=0;j<listConsC.size();j++){
for(i=(get<1>(listConsC[j]))-1;i<get<2>(listConsC[j])-get<0>(listConsC[j])-1;i++){
solver->AddConstraint(solver->MakeGreaterOrEqual(solver->MakeSum(std::vector<IntVar*>(vNoC.begin () + i, vNoC.begin()+ i+get<0>(listConsC[j])+1))->Var(),1));
}
}
}
if(listConsG.size() > 0){
vector<IntVar*> vNoG = vector<IntVar *> (n);
for(i = 1; i <= n; i++){
vNoG[i-1] = solver->MakeIsDifferentCstVar(vSeq[i],2);
}
for(j=0;j<listConsG.size();j++){
for(i=(get<1>(listConsG[j]))-1;i<get<2>(listConsG[j])-get<0>(listConsG[j])-1;i++){
solver->AddConstraint(solver->MakeGreaterOrEqual(solver->MakeSum(std::vector<IntVar*>(vNoG.begin () + i, vNoG.begin()+ i+get<0>(listConsG[j])+1))->Var(),1));
}
}
}
if(listConsU.size() > 0){
vector<IntVar*> vNoU = vector<IntVar *> (n);
for(i = 1; i <= n; i++){
vNoU[i-1] = solver->MakeIsDifferentCstVar(vSeq[i],3);
}
for(j=0;j<listConsU.size();j++){
for(i=(get<1>(listConsU[j]))-1;i<get<2>(listConsU[j])-get<0>(listConsU[j])-1;i++){
solver->AddConstraint(solver->MakeGreaterOrEqual(solver->MakeSum(std::vector<IntVar*>(vNoU.begin () + i, vNoU.begin()+ i+get<0>(listConsU[j])+1))->Var(),1));
}
}
}
}
void IFold::makeBp(int str_index){
int nBPs=0;
vector<IntVar *> str_vBPs;
vector<int> str_BPO;
vector<int> str_BPC;
for (int i=1; i<=n; i++){
if(str_int.at(str_index)[i]>i){
str_BPO.push_back(i);
str_BPC.push_back(str_int.at(str_index)[i]);
str_vBPs.push_back(solver->MakeIntVar(bpdoms, absl::StrFormat("BP_%03d_%03d", str_index,nBPs)));
// cout << "BP[" << nBPs << "] = Seq["<< i << "] - Seq["<< str_int.at(str_index)[i] << "]" << endl;
IntVar* bpShift = solver->MakeIntConst(11);
// REPLACED BY GOLOMB
//solver->AddConstraint(solver->MakeEquality(str_vBPs[nBPs], solver->MakeDifference(solver->MakeElement(golomb,vSeq[i]),solver->MakeElement(golomb,vSeq[str_int.at(str_index)[i]]))->Var()));
solver->AddConstraint(solver->MakeEquality(str_vBPs[nBPs], solver->MakeDifference(vSeqGolomb[i],vSeqGolomb[str_int.at(str_index)[i]])->Var()));
solver->AddConstraint(solver->MakeEquality(vSeq[i], solver->MakeElement(bpToUpO,solver->MakeSum(str_vBPs[nBPs],bpShift)->Var())));
solver->AddConstraint(solver->MakeEquality(vSeq[str_int.at(str_index)[i]], solver->MakeElement(bpToUpC,solver->MakeSum(str_vBPs[nBPs],bpShift)->Var())));
solver->AddConstraint(solver->MakeGreaterOrEqual(solver->MakeSquare(str_vBPs[nBPs]),36));
nBPs++;
}
}
vBPs.push_back(str_vBPs);
BPO.push_back(str_BPO);
BPC.push_back(str_BPC);
}
void IFold::AddCompatibilityConstraint(int* comp_str_int){
if(comp_str_int!= NULL){
int nBPComp=0;
vector<IntVar *> vBPComp;
for (int i=1; i<=n; i++){
if(comp_str_int[i]>i){
vBPComp.push_back(solver->MakeIntVar(bpdoms, absl::StrFormat("BPComp_%03d", nBPComp)));
// cout << "Compatible BP[" << nBPComp << "] = Seq["<< i << "] - Seq["<< comp_str_int[i] << "]" << endl;
// REPLACED BY GOLOMB
// solver->AddConstraint(solver->MakeEquality(vBPComp[nBPComp], solver->MakeDifference(solver->MakeElement(golomb,vSeq[i]),solver->MakeElement(golomb,vSeq[comp_str_int[i]]))->Var()));
solver->AddConstraint(solver->MakeEquality(vBPComp[nBPComp], solver->MakeDifference(vSeqGolomb[i],vSeqGolomb[comp_str_int[i]])->Var()));
// REMOVE
//IntVar* bpShift = solver->MakeIntConst(11);
//solver->AddConstraint(solver->MakeEquality(vSeq[i], solver->MakeElement(bpToUpO,solver->MakeSum(vBPComp[nBPComp],bpShift)->Var()))); // ??
//solver->AddConstraint(solver->MakeEquality(vSeq[comp_str_int[i]], solver->MakeElement(bpToUpC,solver->MakeSum(vBPComp[nBPComp],bpShift)->Var()))); //??
//solver->AddConstraint(solver->MakeGreaterOrEqual(solver->MakeSquare(vBPComp[nBPComp]),36));
nBPComp++;
}
}
}
}
void IFold::AddIncompatibilityConstraint(vector<pair<int,int>> vIncompBP){
for(int i=0;i< vIncompBP.size();i++){
IntVar * vBPIncomp = solver->MakeIntVar(nobpdoms, absl::StrFormat("IncompBP_%03d", i));
// REPLACED BY GOLOMB
//solver->AddConstraint(solver->MakeEquality(vBPIncomp, solver->MakeDifference(solver->MakeElement(golomb,vSeq[vIncompBP[i].first]),solver->MakeElement(golomb,vSeq[vIncompBP[i].second]))->Var()));
solver->AddConstraint(solver->MakeEquality(vBPIncomp, solver->MakeDifference(vSeqGolomb[vIncompBP[i].first],vSeqGolomb[vIncompBP[i].second])->Var()));
// REMOVE
//IntVar* bpShift = solver->MakeIntConst(11);
//solver->AddConstraint(solver->MakeEquality(vSeq[vIncompBP[i].first], solver->MakeElement(bpToUpO,solver->MakeSum(vBPIncomp,bpShift)->Var()))); // ??
//solver->AddConstraint(solver->MakeEquality(vSeq[vIncompBP[i].second], solver->MakeElement(bpToUpC,solver->MakeSum(vBPIncomp,bpShift)->Var()))); //??
//solver->AddConstraint(solver->MakeLess(solver->MakeSquare(vBPIncomp),36));
}
}
void IFold::AddStructureConstraints(int* _str_int, int* _str_int_undet, int includeDangles, double foldTemp, int cutPoint, int MFEstructure, int showHelices, std::vector<HelixCstr> helixCstrs){
int strIndex=str_int.size();
str_int.push_back(_str_int);
str_int_undet.push_back(_str_int_undet);
trgFoldTemps.push_back(foldTemp);
int i;
cutPoint_=cutPoint;
// if(strIndex==0){
// Base pair constraints
makeBp(strIndex);
// }
// else{
// AddCompatibilityConstraint(str_int.at(strIndex));
// }
// Create tree of helices
if(includeDangles){
str_tree.push_back(new StrTree(strIndex,str_int.at(strIndex),n,BPO[strIndex],BPC[strIndex],TH_RNAIFOLD_DANGLES, cutPoint, foldTemp));
}
else{
str_tree.push_back(new StrTree(strIndex,str_int.at(strIndex),n,BPO[strIndex],BPC[strIndex],TH_RNAIFOLD, cutPoint, foldTemp));
}
if(showHelices){
str_tree[str_tree.size()-1]->showTree();
}
// Add MFE structure, energy and ensemble defect contraints
for(i = 0; i < str_tree.at(strIndex)->getHelices().size(); i++){
double minEnergy = NO_ENERGY_LIMIT;
double maxEnergy = NO_ENERGY_LIMIT;
double minED = NO_ED_LIMIT;
double maxED = NO_ED_LIMIT;
for(int j = 0; j < helixCstrs.size(); j++){
if(helixCstrs[j].getTreeId()==strIndex && helixCstrs[j].getHelixId()==i){
switch(helixCstrs[j].getLimitType()){
case HC_ENERGY_MIN: minEnergy = helixCstrs[j].getLimitValue();
break;
case HC_ENERGY_MAX: maxEnergy = helixCstrs[j].getLimitValue();
break;
case HC_ED_MIN: minED = helixCstrs[j].getLimitValue();
break;
case HC_ED_MAX: maxED = helixCstrs[j].getLimitValue();
break;
default: break;
}
}
}
vector<int64> structure(str_tree.at(strIndex)->getHelices()[i]->getJ()-str_tree.at(strIndex)->getHelices()[i]->getI()+2);
structure[0]=str_tree.at(strIndex)->getHelices()[i]->getJ()-str_tree.at(strIndex)->getHelices()[i]->getI()+1;
int strCutPoint = (cutPoint==-1 || cutPoint<str_tree.at(strIndex)->getHelices()[i]->getI() || cutPoint>str_tree.at(strIndex)->getHelices()[i]->getJ()-1)? -1 :(cutPoint-str_tree.at(strIndex)->getHelices()[i]->getI()+2);
if(str_int_undet.at(strIndex) == NULL){
for(int j = str_tree.at(strIndex)->getHelices()[i]->getI(); j <= str_tree.at(strIndex)->getHelices()[i]->getJ(); j++){
if(str_int.at(strIndex)[j]==-1){
structure[j-str_tree.at(strIndex)->getHelices()[i]->getI()+1]=-1;
}
else{
structure[j-str_tree.at(strIndex)->getHelices()[i]->getI()+1]=str_int.at(strIndex)[j]-str_tree.at(strIndex)->getHelices()[i]->getI()+1;
}
}
// MFE constraint
if(MFEstructure){
solver->AddConstraint(solver->RevAlloc(new ViennaConstraintDet(solver, std::vector<IntVar*>(vSeq.begin () + str_tree.at(strIndex)->getHelices()[i]->getI(),
vSeq.begin () + str_tree.at(strIndex)->getHelices()[i]->getJ()+1),
structure,dangles_,rnaLib_,energyModel_,foldTemp, strCutPoint, str_tree.at(strIndex)->getHelices()[i]->getPosLeft()+1, str_tree.at(strIndex)->getHelices()[i]->getJ()-str_tree.at(strIndex)->getHelices()[i]->getI()-str_tree.at(strIndex)->getHelices()[i]->getPosRight()+1,
str_tree.at(strIndex)->getHelices()[i]->getTryLeft() == 1 ? vSeq.at(str_tree.at(strIndex)->getHelices()[i]->getI()-1) : NULL, str_tree.at(strIndex)->getHelices()[i]->getTryRight() == 1 ? vSeq.at(str_tree.at(strIndex)->getHelices()[i]->getJ()+1) : NULL,
maxEnergy, minEnergy)));
}
else{
if(minEnergy != NO_ENERGY_LIMIT || maxEnergy != NO_ENERGY_LIMIT){
solver->AddConstraint(solver->RevAlloc(new EnergyConstraint(solver, std::vector<IntVar*>(vSeq.begin () + str_tree.at(strIndex)->getHelices()[i]->getI(), vSeq.begin () + str_tree.at(strIndex)->getHelices()[i]->getJ()+1), dangles_,rnaLib_,energyModel_,structure, foldTemp, strCutPoint, minEnergy, maxEnergy)));
}
}
if(minED != NO_ED_LIMIT || maxED != NO_ED_LIMIT){
solver->AddConstraint(solver->RevAlloc(new EnsDefConstraint(solver, std::vector<IntVar*>(vSeq.begin () + str_tree.at(strIndex)->getHelices()[i]->getI(), vSeq.begin () + str_tree.at(strIndex)->getHelices()[i]->getJ()+1), dangles_,rnaLib_,energyModel_,structure, foldTemp, strCutPoint, minED, maxED, str_tree.at(strIndex)->getHelices()[i]->getI())));
}
}
else{
for(int j = str_tree.at(strIndex)->getHelices()[i]->getI(); j <= str_tree.at(strIndex)->getHelices()[i]->getJ(); j++){
if(str_int_undet.at(strIndex)[j]<0){
structure[j-str_tree.at(strIndex)->getHelices()[i]->getI()+1]=str_int_undet.at(strIndex)[j];
}
else{
structure[j-str_tree.at(strIndex)->getHelices()[i]->getI()+1]=str_int_undet.at(strIndex)[j]-str_tree.at(strIndex)->getHelices()[i]->getI()+1;
}
}
// MFE constraint
if(MFEstructure){
solver->AddConstraint(solver->RevAlloc(new ViennaConstraintUndet(solver, std::vector<IntVar*>(vSeq.begin () + str_tree.at(strIndex)->getHelices()[i]->getI(),
vSeq.begin () + str_tree.at(strIndex)->getHelices()[i]->getJ()+1),
structure,dangles_,rnaLib_,energyModel_,foldTemp, strCutPoint, str_tree.at(strIndex)->getHelices()[i]->getPosLeft()+1, str_tree.at(strIndex)->getHelices()[i]->getJ()-str_tree.at(strIndex)->getHelices()[i]->getI()-str_tree.at(strIndex)->getHelices()[i]->getPosRight()+1,
str_tree.at(strIndex)->getHelices()[i]->getTryLeft() == 1 ? vSeq.at(str_tree.at(strIndex)->getHelices()[i]->getI()-1) : NULL, str_tree.at(strIndex)->getHelices()[i]->getTryRight() == 1 ? vSeq.at(str_tree.at(strIndex)->getHelices()[i]->getJ()+1) : NULL,
maxEnergy, minEnergy)));
}
else{
if(minEnergy != NO_ENERGY_LIMIT || maxEnergy != NO_ENERGY_LIMIT){
solver->AddConstraint(solver->RevAlloc(new EnergyConstraint(solver, std::vector<IntVar*>(vSeq.begin () + str_tree.at(strIndex)->getHelices()[i]->getI(), vSeq.begin () + str_tree.at(strIndex)->getHelices()[i]->getJ()+1), dangles_,rnaLib_,energyModel_,structure, foldTemp, strCutPoint, minEnergy, maxEnergy)));
}
}
if(minED != NO_ED_LIMIT || maxED != NO_ED_LIMIT){
solver->AddConstraint(solver->RevAlloc(new EnsDefConstraint(solver, std::vector<IntVar*>(vSeq.begin () + str_tree.at(strIndex)->getHelices()[i]->getI(), vSeq.begin () + str_tree.at(strIndex)->getHelices()[i]->getJ()+1), dangles_,rnaLib_,energyModel_,structure, foldTemp, strCutPoint, minED, maxED, str_tree.at(strIndex)->getHelices()[i]->getI())));
}
}
}
}
void IFold::AddLocalStructureConstraints(double foldTemp, int cutPoint, std::vector<LocalCstr> localCstrs){
std::vector<int> visited;
for(int i = 0; i < localCstrs.size(); i++){
if(find(visited.begin(), visited.end(), i) == visited.end()){
double minEnergy = NO_ENERGY_LIMIT;
double maxEnergy = NO_ENERGY_LIMIT;
double minED = NO_ED_LIMIT;
double maxED = NO_ED_LIMIT;
int MFEactive = 0;
visited.push_back(i);
switch(localCstrs[i].getLimitType()){
case LC_ENERGY_MIN: minEnergy = localCstrs[i].getLimitValue();
break;
case LC_ENERGY_MAX: maxEnergy = localCstrs[i].getLimitValue();
break;
case LC_ED_MIN: minED = localCstrs[i].getLimitValue();
break;
case LC_ED_MAX: maxED = localCstrs[i].getLimitValue();
break;
case LC_MFE: MFEactive = 1;
break;
default: break;
}
for(int j = i+1; j < localCstrs.size(); j++){
if(localCstrs[i].isPairedConstraint(localCstrs[j]) && find(visited.begin(), visited.end(), j) == visited.end()){
visited.push_back(j);
switch(localCstrs[j].getLimitType()){
case LC_ENERGY_MIN: minEnergy = localCstrs[j].getLimitValue();
break;
case LC_ENERGY_MAX: maxEnergy = localCstrs[j].getLimitValue();
break;
case LC_ED_MIN: minED = localCstrs[j].getLimitValue();
break;
case LC_ED_MAX: maxED = localCstrs[j].getLimitValue();
break;
case LC_MFE: MFEactive = 1;
break;
default: break;
}
}
}
// Add compatibility constraints for the local structure (solutions must be compatible with the target local structure)
vector<IntVar *> vBPComp;
int nBPComp=0;
for (int j=1; j<=localCstrs[i].getStructureStr().length(); j++){
if(localCstrs[i].getStructureArr()[j]>j){
vBPComp.push_back(solver->MakeIntVar(bpdoms, absl::StrFormat("LocalBPComp_%03d", nBPComp)));
solver->AddConstraint(solver->MakeEquality(vBPComp[nBPComp], solver->MakeDifference(vSeqGolomb[localCstrs[i].getStartPos()+j-1],vSeqGolomb[localCstrs[i].getStartPos()+localCstrs[i].getStructureArr()[j]-1])->Var()));
//cout << "BP Constraint" << (localCstrs[i].getStartPos()+j-1) <<"-"<<(localCstrs[i].getStartPos()+localCstrs[i].getStructureArr()[j]-1) << " " << localCstrs[i].getStructureArr()[j]<< "-"<< j <<endl;
nBPComp++;
}
}
// Adjust cutpoint to the local structure
int strCutPoint = (cutPoint==-1 || cutPoint<localCstrs[i].getStartPos() || cutPoint>localCstrs[i].getStartPos() + localCstrs[i].getStructureStr().length())? -1 :(cutPoint-localCstrs[i].getStartPos()+2);
// If MFE constraint is active energy constraints are included in the Vienna Constraint
if(MFEactive){
if(localCstrs[i].hasUndet()){
solver->AddConstraint(solver->RevAlloc(new ViennaConstraintUndet(solver, std::vector<IntVar*>(vSeq.begin () + localCstrs[i].getStartPos(),
vSeq.begin () + localCstrs[i].getStartPos() + localCstrs[i].getStructureStr().length()),
localCstrs[i].getStructureArr(),dangles_,rnaLib_,energyModel_,foldTemp, strCutPoint, 1, localCstrs[i].getStructureStr().length(),NULL,NULL,maxEnergy, minEnergy)));
}
else{
solver->AddConstraint(solver->RevAlloc(new ViennaConstraintDet(solver, std::vector<IntVar*>(vSeq.begin () + localCstrs[i].getStartPos(),
vSeq.begin () + localCstrs[i].getStartPos() + localCstrs[i].getStructureStr().length()),
localCstrs[i].getStructureArr(),dangles_,rnaLib_,energyModel_,foldTemp, strCutPoint, 1, localCstrs[i].getStructureStr().length(),NULL,NULL,maxEnergy, minEnergy)));
}
}
// If MFE constraint is inactive energy constraint is independent
else{
if(localCstrs[i].hasUndet()){
cout << "Undefined pairing positions are allowed only if MFE contraint is active, otherwise there is no target structure to compute the energy for."<< endl;
exit(1);
}
if(minEnergy != NO_ENERGY_LIMIT || maxEnergy != NO_ENERGY_LIMIT){
solver->AddConstraint(solver->RevAlloc(new EnergyConstraint(solver, std::vector<IntVar*>(vSeq.begin () + localCstrs[i].getStartPos(), vSeq.begin () + localCstrs[i].getStartPos() + localCstrs[i].getStructureStr().length()), dangles_,rnaLib_,energyModel_,localCstrs[i].getStructureArr(), foldTemp, strCutPoint, minEnergy, maxEnergy)));
}
}
// Ad ensemble defect constraints
if(minED != NO_ED_LIMIT || maxED != NO_ED_LIMIT){
solver->AddConstraint(solver->RevAlloc(new EnsDefConstraint(solver, std::vector<IntVar*>(vSeq.begin () + localCstrs[i].getStartPos(), vSeq.begin () + localCstrs[i].getStartPos() + localCstrs[i].getStructureStr().length()), dangles_,rnaLib_,energyModel_,localCstrs[i].getStructureArr(), foldTemp, strCutPoint, minED, maxED, 1)));
}
}
}
return;
}
void IFold::SetSearchHeuristic(int helixHeuristic, int varHeuristic, int randomAssignment, int upthreshold, int bpthreshold){
tree_group = new StrTreeGroup(&str_tree);
vector<int64> order = tree_group->optimizeOrder(helixHeuristic);
// cout << "Final order: " << endl;
// for(int i=0;i<order.size();i++){
// cout << "\t" <<order[i];
// }
// cout << endl;
// string a;
// cin >> a;
vector<vector<int> > BPtypes = tree_group->optimizeValueHeuristic(n,BPO,BPC,str_int, trgFoldTemps);
vector<vector<int> > UPtypes = tree_group->optimizeUPHeuristic(n,BPO,BPC,str_int);
if(BPtypes.size()>1){
varHeuristic = SH_MULTI_STR;
}
upthreshold_=upthreshold;
bpthreshold_=bpthreshold;
switch(varHeuristic){
// No search heuristic, worst case
case SH_NONE:{
for(int i=1;i<=n;i++){
vars.push_back(vSeq[i]);
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_UP_CONTAINS);
var_str.push_back(0);
}
}
break;
// Search by tree levels
case SH_BOTTOM_TO_TOP:{
vector<size_t> orderIndex = tree_group->getOrderIndex();
// Get helices ordered by levels, from highest to lowest
// vector<CPHelix* > sortedHelices = str_tree.at(tree_group->getStrId(i))->getSortedHelices();
for(size_t i :orderIndex){
vector<int> bps = tree_group->getHelix(i)->getBPs();
//Add base pairing positions from inside to outside
for(int j=bps.size()-1; j>=0;j--){
vars.push_back(vBPs.at(tree_group->getStrId(i))[bps[j]]);
// cout << "Adding vBP["<<bps[j]<<"]"<< endl;
if(tree_group->getHelix(i)->isStack(bps[j])){
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_BP_STACK);
}
else{
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_BP);
}
var_str.push_back(tree_group->getStrId(i));
}
vector<int> ups = tree_group->getHelix(i)->getUPs();
//Add unpaired positions
for(int j=0; j<ups.size();j++){
vars.push_back(vSeq[ups[j]]);
// cout << "Adding vSeq["<<ups[j]<<"]"<< endl;
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_UP_CONTAINS);
var_str.push_back(tree_group->getStrId(i));
}
vector<int> cbps = tree_group->getHelix(i)->getClosingBPs();
//Add closing base pairs
for(int j=cbps.size()-1; j>=0;j--){
vars.push_back(vBPs.at(tree_group->getStrId(i))[cbps[j]]);
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_BP);
var_str.push_back(tree_group->getStrId(i));
}
/*
vector<int> positions=tree_group->getHelix(i)->getPositions();
//Add base pairing positions from inside to outside
for(int j=positions.size()-1; j>=0;j--){
if(str_int[positions[j]]!=-1 && str_int[positions[j]]>positions[j]){
vars.push_back(vSeq[positions[j]]);
vars.push_back(vSeq[str_int[positions[j]]]);
}
}
//Add unpaired positions
for(int j=0; j<positions.size();j++){
if(str_int[positions[j]]==-1){
vars.push_back(vSeq[positions[j]]);
}
}
*/
}
}
break;
// Search for multiple structures
case SH_MULTI_STR:{
vector<size_t> orderIndex = tree_group->getOrderIndex();
for(size_t i :orderIndex){
vector<int> bps = tree_group->getHelix(i)->getBPs();
//Add base pairing positions from inside to outside
for(int j=bps.size()-1; j>=0;j--){
vars.push_back(vBPs.at(tree_group->getStrId(i))[bps[j]]);
if(BPtypes.at(tree_group->getStrId(i))[bps[j]] == VH_MULTI_BP_1){
if(tree_group->getHelix(i)->isStack(bps[j])){
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_BP_STACK);
}
else{
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_BP);
}
}
else if(BPtypes.at(tree_group->getStrId(i))[bps[j]] == VH_MULTI_BP_0){
if(tree_group->getHelix(i)->isStack(bps[j])){
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_BP_STACK_INV);
}
else{
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_MULTI_BP_0);
}
}
else{
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : BPtypes.at(tree_group->getStrId(i))[bps[j]]);
}
var_str.push_back(tree_group->getStrId(i));
}
vector<int> ups = tree_group->getHelix(i)->getUPs();
int danglePos = tree_group->getHelix(i)->getPosLeft()+tree_group->getHelix(i)->getPosRight();
//Add unpaired positions
for(int j=0; j<ups.size()-danglePos;j++){
vars.push_back(vSeq[ups[j]]);
// cout << "Adding vSeq["<<ups[j]<<"]"<< endl;
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : UPtypes.at(tree_group->getStrId(i))[ups[j]]);
var_str.push_back(tree_group->getStrId(i));
}
//Add dangles
for(int j=ups.size()-danglePos; j<ups.size();j++){
vars.push_back(vSeq[ups[j]]);
// cout << "Adding dangle vSeq["<<ups[j]<<"]"<< endl;
// If assigning the three prime
if(danglePos == 2 && j==ups.size()-1){
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_THREEP_UP);
}
else{
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : UPtypes.at(tree_group->getStrId(i))[ups[j]]);
}
var_str.push_back(tree_group->getStrId(i));
}
vector<int> cbps = tree_group->getHelix(i)->getClosingBPs();
//Add closing base pairs
for(int j=cbps.size()-1; j>=0;j--){
vars.push_back(vBPs.at(tree_group->getStrId(i))[cbps[j]]);
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_MULTI_BP_1);
var_str.push_back(tree_group->getStrId(i));
}
}
}
break;
// Search by tree levels
case SH_BOTTOM_TO_TOP_BAK:{
// Get helices ordered by levels, from highest to lowest
vector<CPHelix* > sortedHelices = str_tree.at(0)->getSortedHelices();
for(int i=0; i <sortedHelices.size();i++){
vector<int> bps = sortedHelices[i]->getBPs();
//Add base pairing positions from inside to outside
for(int j=bps.size()-1; j>=0;j--){
vars.push_back(vBPs.at(0)[bps[j]]);
// cout << "Adding vBP["<<bps[j]<<"]"<< endl;
if(sortedHelices[i]->isStack(bps[j])){
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_BP_STACK);
}
else{
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_BP);
}
var_str.push_back(tree_group->getStrId(0));
}
vector<int> cbps = sortedHelices[i]->getClosingBPs();
//Add closing base pairs
for(int j=cbps.size()-1; j>=0;j--){
vars.push_back(vBPs.at(0)[cbps[j]]);
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_BP);
var_str.push_back(tree_group->getStrId(0));
}
vector<int> ups = sortedHelices[i]->getUPs();
//Add unpaired positions
for(int j=0; j<ups.size();j++){
vars.push_back(vSeq[ups[j]]);
// cout << "Adding vSeq["<<ups[j]<<"]"<< endl;
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_UP_CONTAINS);
var_str.push_back(tree_group->getStrId(0));
}
/*
vector<int> positions=sortedHelices[i]->getPositions();
//Add base pairing positions from inside to outside
for(int j=positions.size()-1; j>=0;j--){
if(str_int[positions[j]]!=-1 && str_int[positions[j]]>positions[j]){
vars.push_back(vSeq[positions[j]]);
vars.push_back(vSeq[str_int[positions[j]]]);
}
}
//Add unpaired positions
for(int j=0; j<positions.size();j++){
if(str_int[positions[j]]==-1){
vars.push_back(vSeq[positions[j]]);
}
}
*/
}
}
break;
case SH_BOTTOM_TO_TOP_UP:{
// Get helices ordered by levels, from highest to lowest
vector<CPHelix* > sortedHelices = str_tree.at(0)->getSortedHelices();
for(int i=0; i <sortedHelices.size();i++){
vector<int> bps = sortedHelices[i]->getBPs();
//Add base pairing positions from inside to outside
for(int j=bps.size()-1; j>=0;j--){
vars.push_back(vBPs.at(0)[bps[j]]);
//cout << "Adding vBP["<<bps[j]<<"]"<< endl;
if(sortedHelices[i]->isStack(bps[j])){
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_BP_STACK);
}
else{
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_BP);
}
var_str.push_back(tree_group->getStrId(0));
}
vector<int> ups = sortedHelices[i]->getUPs();
//Add unpaired positions
for(int j=0; j<ups.size();j++){
vars.push_back(vSeq[ups[j]]);
//cout << "Adding vSeq["<<ups[j]<<"]"<< endl;
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_UP_CONTAINS);
var_str.push_back(tree_group->getStrId(0));
}
}
}
break;
// Default, from inner to outer stems
case SH_IN_TO_OUT:
default:
vector<bool> used(n+1,false);
for (int d = SIGMA+1; d <= n; d++){
for(int i=1; (i+d<=n); i++){
int j=i+d;
if(str_int.at(0)[i]==j){
for(int l=0;l<BPO.at(0).size();l++){
if(BPO.at(0)[l]==i){
vars.push_back(vBPs.at(0)[l]);
if(str_int.at(0)[i+1]==j-1){
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_BP_STACK);
}
else{
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_BP);
}
var_str.push_back(tree_group->getStrId(0));
used[i] = true;
used[j] = true;
for(int k=i+1;k<j;k++){
if(!used[k]&&str_int.at(0)[k]==-1){
vars.push_back(vSeq[k]);
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_UP_CONTAINS);
var_str.push_back(tree_group->getStrId(0));
used[k] = true;
}
}
}
}
/* vars.push_back(vSeq[i]);
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_UP_CONTAINS);
vars.push_back(vSeq[j]);
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_UP_CONTAINS);
used[i] = true;
used[j] = true;
for(int k=i+1;k<j;k++){
if(!used[k]&&str_int[k]==-1){
vars.push_back(vSeq[k]);
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_UP_CONTAINS);
used[k] = true;
}
}*/
}
}
}
// Set remaining positions (external loops)
for(int i=1;i<=n;i++){
if(!used[i]){
vars.push_back(vSeq[i]);
var_types.push_back(randomAssignment != 0 ? VH_RANDOM : VH_UP_CONTAINS);
var_str.push_back(tree_group->getStrId(0));
}
}
break;
}
}
void IFold::Search(int maxSolutions, int64 timeLimit, int minimizeMFE, int minimizeEnsDef, int LNS, int LNSunchangedRestarts, int LNSrestartTime, int showMeasures){
int i;
BaseAssignVariables* const db = MakePhase(solver,vars,var_types, upthreshold_, bpthreshold_);
std::vector<SearchMonitor*> monitors;
SolutionCollector* collector;
// UNCOMMENT TO ACTIVATE LOG MONITOR
//SearchMonitor* const log = solver->MakeSearchLog(100000);
//monitors.push_back(log);
//SearchMonitor* const log = solver->MakeSearchTrace("EEEEEEEEEE");
//monitors.push_back(log);
// UNCOMMENT TO PRINT SEARCH TREE
//SearchMonitor* const cpviz = solver->MakeTreeMonitor(vars, "tree.xml","visualization.xml");
//monitors.push_back(cpviz);
// Variables for diversity measures
vector<RNAPlugin*> measuresVienna;
vector<string> targetStructures;
vector<int*> str_int_0index;
for(i=0;i<str_int.size();i++){
string targetStr="";
measuresVienna.push_back(newRNAplugin(rnaLib_,n,dangles_));
measuresVienna.at(i)->setEnergyModel(energyModel_);
measuresVienna.at(i)->setCutPoint(cutPoint_);
measuresVienna.at(i)->setTemperature(trgFoldTemps.at(i));
str_int_0index.push_back((int*) malloc(sizeof(int)*(n)));
targetStructures.push_back(targetStr);
}
//if(showMeasures>0){
for(int j=0;j<str_int.size();j++){
for(i=1;i<=n;i++){
if(str_int.at(j)[i]==-1){
str_int_0index.at(j)[i-1]=-1;
targetStructures.at(j).append(".");
}
else{
str_int_0index.at(j)[i-1]=str_int.at(j)[i]-1;
if(str_int.at(j)[i]>i){
targetStructures.at(j).append("(");
}
else{
targetStructures.at(j).append(")");
}
}
}
measuresVienna.at(j)->setTestStructure(targetStructures.at(j));
}
//}
IntVar* blosumScore;
// Maximize blosum similarity monitor
if(maxBlosumValue > 0){
blosumScore = solver->MakeSum(vAaSeqSimilarity)->Var();
OptimizeVar* opBlosumScore;
opBlosumScore = solver->MakeMaximize(blosumScore,1);
monitors.push_back(opBlosumScore);
}
// LNS restart monitor
SearchMonitor* restartMonitor;
if(LNS>0){
restartMonitor=MakeLNSRestart(solver,db, vSeq, str_int, dangles_,rnaLib_,energyModel_,trgFoldTemps, LNSrestartTime, LNSunchangedRestarts,tree_group);
monitors.push_back(restartMonitor);
}
// Time limit monitor
SearchLimit* limit = NULL;
//clock_t begin_search = clock();
if(timeLimit>0){
// Search limit.
limit = solver->MakeTimeLimit(timeLimit);
monitors.push_back(limit);
}
// Energy minimization constraint (for all structures)
if(minimizeMFE==1){
for(i =0; i< str_int.size();i++){
MinEnergyConstraint* mfeConst = new MinEnergyConstraint(solver, std::vector<IntVar*>(vSeq.begin () +1,vSeq.end()),dangles_,rnaLib_,energyModel_,((str_int_undet.at(i)==NULL) ? targetStructures.at(i) : "") ,trgFoldTemps.at(i), cutPoint_);
solver->AddConstraint(solver->RevAlloc(mfeConst));
monitors.push_back(mfeConst->obj);
}
}
// Ensemble defect minimization constraint (for all structures)
if(minimizeEnsDef==1){
for(i =0; i< str_int.size();i++){
MinEnsDefConstraint* minEdConst = new MinEnsDefConstraint(solver, std::vector<IntVar*>(vSeq.begin () +1,vSeq.end()),dangles_,rnaLib_,energyModel_,((str_int_undet.at(i)==NULL) ? str_int_0index.at(i) : NULL), trgFoldTemps.at(i), cutPoint_);
solver->AddConstraint(solver->RevAlloc(minEdConst));
monitors.push_back(minEdConst->obj);
}
}
int nSolutions =0;
solver->NewSearch(db,monitors);
while (solver->NextSolution() && (maxSolutions==0 || nSolutions<maxSolutions)) {
nSolutions++;
string outSequence ="";
for(i=1;i<=n;i++)
outSequence+=ToNucl(vSeq[i]->Value());