--- /dev/null
+/* Last changed Time-stamp: <2007-08-26 11:59:45 ivo> */
+/*
+ compute the duplex structure of two RNA strands,
+ allowing only inter-strand base pairs.
+ see cofold() for computing hybrid structures without
+ restriction.
+
+ Ivo Hofacker
+ Vienna RNA package
+*/
+
+#include <config.h>
+#include <stdio.h>
+#include <stdlib.h>
+#include <math.h>
+#include <ctype.h>
+#include <string.h>
+#include "utils.h"
+#include "energy_par.h"
+#include "fold_vars.h"
+#include "fold.h"
+#include "pair_mat.h"
+#include "params.h"
+#include "alifold.h"
+#include "subopt.h"
+#include "loop_energies.h"
+#include "duplex.h"
+
+#ifdef _OPENMP
+#include <omp.h>
+#endif
+
+/*@unused@*/
+static char rcsid[] UNUSED = "$Id: duplex.c,v 1.8 2007/08/26 10:08:44 ivo Exp $";
+
+#define STACK_BULGE1 1 /* stacking energies for bulges of size 1 */
+#define NEW_NINIO 1 /* new asymetry penalty */
+#define MAXSECTORS 500 /* dimension for a backtrack array */
+#define LOCALITY 0. /* locality parameter for base-pairs */
+#define UNIT 100
+#define MINPSCORE -2 * UNIT
+#define NONE -10000 /* score for forbidden pairs */
+
+
+
+/*
+#################################
+# GLOBAL VARIABLES #
+#################################
+*/
+/*
+#################################
+# PRIVATE VARIABLES #
+#################################
+*/
+PRIVATE paramT *P = NULL;
+PRIVATE int **c = NULL; /* energy array, given that i-j pair */
+PRIVATE short *S1 = NULL, *SS1 = NULL, *S2 = NULL, *SS2 = NULL;
+PRIVATE int n1,n2; /* sequence lengths */
+
+#ifdef _OPENMP
+
+/* NOTE: all variables are assumed to be uninitialized if they are declared as threadprivate
+*/
+#pragma omp threadprivate(P, c, S1, SS1, S2, SS2, n1, n2)
+
+#endif
+
+/*
+#################################
+# PRIVATE FUNCTION DECLARATIONS #
+#################################
+*/
+PRIVATE duplexT duplexfold_cu(const char *s1, const char *s2, int clean_up);
+PRIVATE duplexT aliduplexfold_cu(const char *s1[], const char *s2[], int clean_up);
+PRIVATE char *backtrack(int i, int j);
+PRIVATE char *alibacktrack(int i, int j, const short **S1, const short **S2);
+PRIVATE int compare(const void *sub1, const void *sub2);
+PRIVATE int covscore(const int *types, int n_seq);
+
+/*
+#################################
+# BEGIN OF FUNCTION DEFINITIONS #
+#################################
+*/
+
+PUBLIC duplexT duplexfold(const char *s1, const char *s2){
+ return duplexfold_cu(s1, s2, 1);
+}
+
+PRIVATE duplexT duplexfold_cu(const char *s1, const char *s2, int clean_up){
+ int i, j, l1, Emin=INF, i_min=0, j_min=0;
+ char *struc;
+ duplexT mfe;
+
+ n1 = (int) strlen(s1);
+ n2 = (int) strlen(s2);
+
+ if ((!P) || (fabs(P->temperature - temperature)>1e-6)) {
+ if(P) free(P); P = scale_parameters();
+ make_pair_matrix();
+ }
+
+ c = (int **) space(sizeof(int *) * (n1+1));
+ for (i=1; i<=n1; i++) c[i] = (int *) space(sizeof(int) * (n2+1));
+
+ S1 = encode_sequence(s1, 0);
+ S2 = encode_sequence(s2, 0);
+ SS1 = encode_sequence(s1, 1);
+ SS2 = encode_sequence(s2, 1);
+
+ for (i=1; i<=n1; i++) {
+ for (j=n2; j>0; j--) {
+ int type, type2, E, k,l;
+ type = pair[S1[i]][S2[j]];
+ c[i][j] = type ? P->DuplexInit : INF;
+ if (!type) continue;
+ c[i][j] += E_ExtLoop(type, (i>1) ? SS1[i-1] : -1, (j<n2) ? SS2[j+1] : -1, P);
+ for (k=i-1; k>0 && k>i-MAXLOOP-2; k--) {
+ for (l=j+1; l<=n2; l++) {
+ if (i-k+l-j-2>MAXLOOP) break;
+ type2 = pair[S1[k]][S2[l]];
+ if (!type2) continue;
+ E = E_IntLoop(i-k-1, l-j-1, type2, rtype[type],
+ SS1[k+1], SS2[l-1], SS1[i-1], SS2[j+1], P);
+ c[i][j] = MIN2(c[i][j], c[k][l]+E);
+ }
+ }
+ E = c[i][j];
+ E += E_ExtLoop(rtype[type], (j > 1) ? SS2[j-1] : -1, (i<n1) ? SS1[i+1] : -1, P);
+ if (E<Emin) {
+ Emin=E; i_min=i; j_min=j;
+ }
+ }
+ }
+
+ struc = backtrack(i_min, j_min);
+ if (i_min<n1) i_min++;
+ if (j_min>1 ) j_min--;
+ l1 = strchr(struc, '&')-struc;
+ /*
+ printf("%s %3d,%-3d : %3d,%-3d (%5.2f)\n", struc, i_min+1-l1, i_min,
+ j_min, j_min+strlen(struc)-l1-2, Emin*0.01);
+ */
+ mfe.i = i_min;
+ mfe.j = j_min;
+ mfe.energy = (float) Emin/100.;
+ mfe.structure = struc;
+ if(clean_up) {
+ for (i=1; i<=n1; i++) free(c[i]);
+ free(c);
+ free(S1);
+ free(S2);
+ free(SS1);
+ free(SS2);
+ }
+ return mfe;
+}
+
+PUBLIC duplexT *duplex_subopt(const char *s1, const char *s2, int delta, int w) {
+ int i,j, n1, n2, thresh, E, n_subopt=0, n_max;
+ char *struc;
+ duplexT mfe;
+ duplexT *subopt;
+
+ n_max=16;
+ subopt = (duplexT *) space(n_max*sizeof(duplexT));
+ mfe = duplexfold_cu(s1, s2, 0);
+ free(mfe.structure);
+
+ thresh = (int) mfe.energy*100+0.1 + delta;
+ n1 = strlen(s1); n2=strlen(s2);
+ for (i=n1; i>0; i--) {
+ for (j=1; j<=n2; j++) {
+ int type, ii,jj, Ed;
+ type = pair[S2[j]][S1[i]];
+ if (!type) continue;
+ E = Ed = c[i][j];
+ Ed += E_ExtLoop(type, (j>1) ? SS2[j-1] : -1, (i<n1) ? SS1[i+1] : -1, P);
+ if (Ed>thresh) continue;
+ /* too keep output small, remove hits that are dominated by a
+ better one close (w) by. For simplicity we do test without
+ adding dangles, which is slightly inaccurate.
+ */
+ for (ii=MAX2(i-w,1); (ii<=MIN2(i+w,n1)) && type; ii++) {
+ for (jj=MAX2(j-w,1); jj<=MIN2(j+w,n2); jj++)
+ if (c[ii][jj]<E) {type=0; break;}
+ }
+ if (!type) continue;
+
+ struc = backtrack(i,j);
+ fprintf(stderr, "%d %d %d\n", i,j,E);
+ if (n_subopt+1>=n_max) {
+ n_max *= 2;
+ subopt = (duplexT *) xrealloc(subopt, n_max*sizeof(duplexT));
+ }
+ subopt[n_subopt].i = MIN2(i+1,n1);
+ subopt[n_subopt].j = MAX2(j-1,1);
+ subopt[n_subopt].energy = Ed * 0.01;
+ subopt[n_subopt++].structure = struc;
+ }
+ }
+ /* free all static globals */
+ for (i=1; i<=n1; i++) free(c[i]);
+ free(c);
+ free(S1); free(S2); free(SS1); free(SS2);
+
+ if (subopt_sorted) qsort(subopt, n_subopt, sizeof(duplexT), compare);
+ subopt[n_subopt].i =0;
+ subopt[n_subopt].j =0;
+ subopt[n_subopt].structure = NULL;
+ return subopt;
+}
+
+PRIVATE char *backtrack(int i, int j) {
+ /* backtrack structure going backwards from i, and forwards from j
+ return structure in bracket notation with & as separator */
+ int k, l, type, type2, E, traced, i0, j0;
+ char *st1, *st2, *struc;
+
+ st1 = (char *) space(sizeof(char)*(n1+1));
+ st2 = (char *) space(sizeof(char)*(n2+1));
+
+ i0=MIN2(i+1,n1); j0=MAX2(j-1,1);
+
+ while (i>0 && j<=n2) {
+ E = c[i][j]; traced=0;
+ st1[i-1] = '(';
+ st2[j-1] = ')';
+ type = pair[S1[i]][S2[j]];
+ if (!type) nrerror("backtrack failed in fold duplex");
+ for (k=i-1; k>0 && k>i-MAXLOOP-2; k--) {
+ for (l=j+1; l<=n2; l++) {
+ int LE;
+ if (i-k+l-j-2>MAXLOOP) break;
+ type2 = pair[S1[k]][S2[l]];
+ if (!type2) continue;
+ LE = E_IntLoop(i-k-1, l-j-1, type2, rtype[type],
+ SS1[k+1], SS2[l-1], SS1[i-1], SS2[j+1], P);
+ if (E == c[k][l]+LE) {
+ traced=1;
+ i=k; j=l;
+ break;
+ }
+ }
+ if (traced) break;
+ }
+ if (!traced) {
+ E -= E_ExtLoop(type, (i>1) ? SS1[i-1] : -1, (j<n2) ? SS2[j+1] : -1, P);
+ if (E != P->DuplexInit) {
+ nrerror("backtrack failed in fold duplex");
+ } else break;
+ }
+ }
+ if (i>1) i--;
+ if (j<n2) j++;
+
+ struc = (char *) space(i0-i+1+j-j0+1+2);
+ for (k=MAX2(i,1); k<=i0; k++) if (!st1[k-1]) st1[k-1] = '.';
+ for (k=j0; k<=j; k++) if (!st2[k-1]) st2[k-1] = '.';
+ strcpy(struc, st1+MAX2(i-1,0)); strcat(struc, "&");
+ strcat(struc, st2+j0-1);
+
+ /* printf("%s %3d,%-3d : %3d,%-3d\n", struc, i,i0,j0,j); */
+ free(st1); free(st2);
+
+ return struc;
+}
+
+/*------------------------------------------------------------------------*/
+
+PRIVATE int compare(const void *sub1, const void *sub2) {
+ int d;
+ if (((duplexT *) sub1)->energy > ((duplexT *) sub2)->energy)
+ return 1;
+ if (((duplexT *) sub1)->energy < ((duplexT *) sub2)->energy)
+ return -1;
+ d = ((duplexT *) sub1)->i - ((duplexT *) sub2)->i;
+ if (d!=0) return d;
+ return ((duplexT *) sub1)->j - ((duplexT *) sub2)->j;
+}
+
+/*---------------------------------------------------------------------------*/
+
+PUBLIC duplexT aliduplexfold(const char *s1[], const char *s2[]){
+ return aliduplexfold_cu(s1, s2, 1);
+}
+
+PRIVATE duplexT aliduplexfold_cu(const char *s1[], const char *s2[], int clean_up) {
+ int i, j, s, n_seq, l1, Emin=INF, i_min=0, j_min=0;
+ char *struc;
+ duplexT mfe;
+ short **S1, **S2;
+ int *type;
+ n1 = (int) strlen(s1[0]);
+ n2 = (int) strlen(s2[0]);
+
+ for (s=0; s1[s]!=NULL; s++);
+ n_seq = s;
+ for (s=0; s2[s]!=NULL; s++);
+ if (n_seq != s) nrerror("unequal number of sequences in aliduplexfold()\n");
+
+ if ((!P) || (fabs(P->temperature - temperature)>1e-6)) {
+ if(P) free(P); P = scale_parameters();
+ make_pair_matrix();
+ }
+
+ c = (int **) space(sizeof(int *) * (n1+1));
+ for (i=1; i<=n1; i++) c[i] = (int *) space(sizeof(int) * (n2+1));
+
+ S1 = (short **) space((n_seq+1)*sizeof(short *));
+ S2 = (short **) space((n_seq+1)*sizeof(short *));
+ for (s=0; s<n_seq; s++) {
+ if (strlen(s1[s]) != n1) nrerror("uneqal seqence lengths");
+ if (strlen(s2[s]) != n2) nrerror("uneqal seqence lengths");
+ S1[s] = encode_sequence(s1[s], 0);
+ S2[s] = encode_sequence(s2[s], 0);
+ }
+ type = (int *) space(n_seq*sizeof(int));
+
+ for (i=1; i<=n1; i++) {
+ for (j=n2; j>0; j--) {
+ int k,l,E,psc;
+ for (s=0; s<n_seq; s++) {
+ type[s] = pair[S1[s][i]][S2[s][j]];
+ }
+ psc = covscore(type, n_seq);
+ for (s=0; s<n_seq; s++) if (type[s]==0) type[s]=7;
+ c[i][j] = (psc>=MINPSCORE) ? (n_seq*P->DuplexInit) : INF;
+ if (psc<MINPSCORE) continue;
+ for(s=0; s<n_seq;s++){
+ c[i][j] += E_ExtLoop(type[s], (i>1) ? S1[s][i-1] : -1, (j<n2) ? S2[s][j+1] : -1, P);
+ }
+ for (k=i-1; k>0 && k>i-MAXLOOP-2; k--) {
+ for (l=j+1; l<=n2; l++) {
+ int type2;
+ if (i-k+l-j-2>MAXLOOP) break;
+ if (c[k][l]>INF/2) continue;
+ for (E=s=0; s<n_seq; s++) {
+ type2 = pair[S1[s][k]][S2[s][l]];
+ if (type2==0) type2=7;
+ E += E_IntLoop(i-k-1, l-j-1, type2, rtype[type[s]],
+ S1[s][k+1], S2[s][l-1], S1[s][i-1], S2[s][j+1], P);
+ }
+ c[i][j] = MIN2(c[i][j], c[k][l]+E);
+ }
+ }
+ c[i][j] -= psc;
+ E = c[i][j];
+ for (s=0; s<n_seq; s++) {
+ E += E_ExtLoop(rtype[type[s]], (j>1) ? S2[s][j-1] : -1, (i<n1) ? S1[s][i+1] : -1, P);
+ }
+ if (E<Emin) {
+ Emin=E; i_min=i; j_min=j;
+ }
+ }
+ }
+
+ struc = alibacktrack(i_min, j_min, (const short **)S1,(const short **)S2);
+ if (i_min<n1) i_min++;
+ if (j_min>1 ) j_min--;
+ l1 = strchr(struc, '&')-struc;
+ /*
+ printf("%s %3d,%-3d : %3d,%-3d (%5.2f)\n", struc, i_min+1-l1, i_min,
+ j_min, j_min+strlen(struc)-l1-2, Emin*0.01);
+ */
+ mfe.i = i_min;
+ mfe.j = j_min;
+ mfe.energy = (float) (Emin/(100.*n_seq));
+ mfe.structure = struc;
+ if (clean_up){
+ for (i=1; i<=n1; i++) free(c[i]);
+ free(c);
+ }
+ for (s=0; s<n_seq; s++) {
+ free(S1[s]); free(S2[s]);
+ }
+ free(S1);
+ free(S2);
+ free(type);
+ return mfe;
+}
+
+PUBLIC duplexT *aliduplex_subopt(const char *s1[], const char *s2[], int delta, int w) {
+ int i,j, n1, n2, thresh, E, n_subopt=0, n_max, s, n_seq, *type;
+ char *struc;
+ duplexT mfe;
+ duplexT *subopt;
+ short **S1, **S2;
+
+ n_max=16;
+ subopt = (duplexT *) space(n_max*sizeof(duplexT));
+ mfe = aliduplexfold_cu(s1, s2, 0);
+ free(mfe.structure);
+
+ for (s=0; s1[s]!=NULL; s++);
+ n_seq = s;
+
+ thresh = (int) ((mfe.energy*100. + delta)*n_seq +0.1);
+ n1 = strlen(s1[0]); n2=strlen(s2[0]);
+ S1 = (short **) space((n_seq+1)*sizeof(short *));
+ S2 = (short **) space((n_seq+1)*sizeof(short *));
+ for (s=0; s<n_seq; s++) {
+ if (strlen(s1[s]) != n1) nrerror("uneqal seqence lengths");
+ if (strlen(s2[s]) != n2) nrerror("uneqal seqence lengths");
+ S1[s] = encode_sequence(s1[s], 0);
+ S2[s] = encode_sequence(s2[s], 0);
+ }
+ type = (int *) space(n_seq*sizeof(int));
+
+ for (i=n1; i>0; i--) {
+ for (j=1; j<=n2; j++) {
+ int ii, jj, skip, Ed, psc;
+
+ for (s=0; s<n_seq; s++) {
+ type[s] = pair[S2[s][j]][S1[s][i]];
+ }
+ psc = covscore(type, n_seq);
+ for (s=0; s<n_seq; s++) if (type[s]==0) type[s]=7;
+ if (psc<MINPSCORE) continue;
+ E = Ed = c[i][j];
+ for (s=0; s<n_seq; s++) {
+ Ed += E_ExtLoop(type[s], (j>1) ? S2[s][j-1] : -1, (i<n1) ? S1[s][i+1] : -1, P);
+ }
+ if (Ed>thresh) continue;
+ /* too keep output small, skip hits that are dominated by a
+ better one close (w) by. For simplicity we don't take dangels
+ into account here, thus the heuristic is somewhat inaccurate.
+ */
+ for (skip=0, ii=MAX2(i-w,1); (ii<=MIN2(i+w,n1)) && type; ii++) {
+ for (jj=MAX2(j-w,1); jj<=MIN2(j+w,n2); jj++)
+ if (c[ii][jj]<E) {skip=1; break;}
+ }
+ if (skip) continue;
+ struc = alibacktrack(i,j,(const short **)S1, (const short **)S2);
+ fprintf(stderr, "%d %d %d\n", i,j,E);
+ if (n_subopt+1>=n_max) {
+ n_max *= 2;
+ subopt = (duplexT *) xrealloc(subopt, n_max*sizeof(duplexT));
+ }
+ subopt[n_subopt].i = MIN2(i+1,n1);
+ subopt[n_subopt].j = MAX2(j-1,1);
+ subopt[n_subopt].energy = Ed * 0.01/n_seq;
+ subopt[n_subopt++].structure = struc;
+ }
+ }
+
+ for (i=1; i<=n1; i++) free(c[i]);
+ free(c);
+ for (s=0; s<n_seq; s++) {
+ free(S1[s]); free(S2[s]);
+ }
+ free(S1); free(S2); free(type);
+
+ if (subopt_sorted) qsort(subopt, n_subopt, sizeof(duplexT), compare);
+ subopt[n_subopt].i =0;
+ subopt[n_subopt].j =0;
+ subopt[n_subopt].structure = NULL;
+ return subopt;
+}
+
+PRIVATE char *alibacktrack(int i, int j, const short **S1, const short **S2) {
+ /* backtrack structure going backwards from i, and forwards from j
+ return structure in bracket notation with & as separator */
+ int k, l, *type, type2, E, traced, i0, j0, s, n_seq;
+ char *st1, *st2, *struc;
+
+ n1 = (int) S1[0][0];
+ n2 = (int) S2[0][0];
+
+ for (s=0; S1[s]!=NULL; s++);
+ n_seq = s;
+ for (s=0; S2[s]!=NULL; s++);
+ if (n_seq != s) nrerror("unequal number of sequences in alibacktrack()\n");
+
+ st1 = (char *) space(sizeof(char)*(n1+1));
+ st2 = (char *) space(sizeof(char)*(n2+1));
+ type = (int *) space(n_seq*sizeof(int));
+
+ i0=MIN2(i+1,n1); j0=MAX2(j-1,1);
+
+ while (i>0 && j<=n2) {
+ int psc;
+ E = c[i][j]; traced=0;
+ st1[i-1] = '(';
+ st2[j-1] = ')';
+ for (s=0; s<n_seq; s++) {
+ type[s] = pair[S1[s][i]][S2[s][j]];
+ }
+ psc = covscore(type, n_seq);
+ for (s=0; s<n_seq; s++) if (type[s]==0) type[s] = 7;
+ E += psc;
+ for (k=i-1; k>0 && k>i-MAXLOOP-2; k--) {
+ for (l=j+1; l<=n2; l++) {
+ int LE;
+ if (i-k+l-j-2>MAXLOOP) break;
+ if (c[k][l]>INF/2) continue;
+ for (s=LE=0; s<n_seq; s++) {
+ type2 = pair[S1[s][k]][S2[s][l]];
+ if (type2==0) type2=7;
+ LE += E_IntLoop(i-k-1, l-j-1, type2, rtype[type[s]],
+ S1[s][k+1], S2[s][l-1], S1[s][i-1], S2[s][j+1], P);
+ }
+ if (E == c[k][l]+LE) {
+ traced=1;
+ i=k; j=l;
+ break;
+ }
+ }
+ if (traced) break;
+ }
+ if (!traced) {
+ for (s=0; s<n_seq; s++) {
+ E -= E_ExtLoop(type[s], (i>1) ? S1[s][i-1] : -1, (j<n2) ? S2[s][j+1] : -1, P);
+ }
+ if (E != n_seq*P->DuplexInit) {
+ nrerror("backtrack failed in aliduplex");
+ } else break;
+ }
+ }
+ if (i>1) i--;
+ if (j<n2) j++;
+
+ struc = (char *) space(i0-i+1+j-j0+1+2);
+ for (k=MAX2(i,1); k<=i0; k++) if (!st1[k-1]) st1[k-1] = '.';
+ for (k=j0; k<=j; k++) if (!st2[k-1]) st2[k-1] = '.';
+ strcpy(struc, st1+MAX2(i-1,0)); strcat(struc, "&");
+ strcat(struc, st2+j0-1);
+
+ /* printf("%s %3d,%-3d : %3d,%-3d\n", struc, i,i0,j0,j); */
+ free(st1); free(st2); free(type);
+
+ return struc;
+}
+
+
+PRIVATE int covscore(const int *types, int n_seq) {
+ /* calculate co-variance bonus for a pair depending on */
+ /* compensatory/consistent mutations and incompatible seqs */
+ /* should be 0 for conserved pairs, >0 for good pairs */
+ int k,l,s,score, pscore;
+ int dm[7][7]={{0,0,0,0,0,0,0}, /* hamming distance between pairs */
+ {0,0,2,2,1,2,2} /* CG */,
+ {0,2,0,1,2,2,2} /* GC */,
+ {0,2,1,0,2,1,2} /* GU */,
+ {0,1,2,2,0,2,1} /* UG */,
+ {0,2,2,1,2,0,2} /* AU */,
+ {0,2,2,2,1,2,0} /* UA */};
+
+ int pfreq[8]={0,0,0,0,0,0,0,0};
+ for (s=0; s<n_seq; s++)
+ pfreq[types[s]]++;
+
+ if (pfreq[0]*2>n_seq) return NONE;
+ for (k=1,score=0; k<=6; k++) /* ignore pairtype 7 (gap-gap) */
+ for (l=k+1; l<=6; l++)
+ /* scores for replacements between pairtypes */
+ /* consistent or compensatory mutations score 1 or 2 */
+ score += pfreq[k]*pfreq[l]*dm[k][l];
+
+ /* counter examples score -1, gap-gap scores -0.25 */
+ pscore = cv_fact *
+ ((UNIT*score)/n_seq - nc_fact*UNIT*(pfreq[0] + pfreq[7]*0.25));
+ return pscore;
+}
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