/* Last changed Time-stamp: <2007-05-09 16:11:21 ivo> */
/*
partiton function for RNA secondary structures
Ivo L Hofacker
Stephan Bernhart
Vienna RNA package
*/
/*
$Log: part_func_co.c,v $
Revision 1.10 2007/05/10 17:27:01 ivo
make sure the relative error eps is positive in newton iteration
Revision 1.9 2006/05/10 15:12:11 ivo
some compiler choked on double semicolon after declaration
Revision 1.8 2006/04/05 12:52:31 ivo
Fix performance bug (O(n^4) loop)
Revision 1.7 2006/01/19 11:30:04 ivo
compute_probabilities should only look at one dimer at a time
Revision 1.6 2006/01/18 12:55:40 ivo
major cleanup of berni code
fix bugs related to confusing which free energy is returned by co_pf_fold()
Revision 1.5 2006/01/16 11:32:25 ivo
small bug in multiloop pair probs
Revision 1.4 2006/01/05 18:13:40 ivo
update
Revision 1.3 2006/01/04 15:14:29 ivo
fix bug in concentration calculations
Revision 1.2 2004/12/23 12:14:41 berni
*** empty log message ***
Revision 1.1 2004/12/22 10:46:17 berni
Partition function Cofolding 0.9, Computation of concentrations.
Revision 1.16 2003/08/04 09:14:09 ivo
finish up stochastic backtracking
Revision 1.15 2002/03/19 16:51:12 ivo
more on stochastic backtracking (still incomplete)
Revision 1.13 2001/11/16 17:30:04 ivo
add stochastic backtracking (still incomplete)
*/
#include <config.h>
#include <stdio.h>
#include <stdlib.h>
#include <string.h>
#include <math.h>
#include <float.h> /* #defines FLT_MAX ... */
#include <limits.h>
#include "utils.h"
#include "energy_par.h"
#include "fold_vars.h"
#include "pair_mat.h"
#include "PS_dot.h"
#include "params.h"
#include "loop_energies.h"
#include "part_func.h"
#include "part_func_co.h"
#ifdef _OPENMP
#include <omp.h>
#endif
/*@unused@*/
PRIVATE char rcsid[] UNUSED = "$Id: part_func_co.c,v 1.10 2007/05/10 17:27:01 ivo Exp $";
#define ISOLATED 256.0
#undef TURN
#define TURN 0
#define SAME_STRAND(I,J) (((I)>=cut_point)||((J)<cut_point))
/* #define SAME_STRAND(I,J) (((J)<cut_point)||((I)>=cut_point2)||(((I)>=cut_point)&&((J)<cut_point2)))
*/
/*
#################################
# GLOBAL VARIABLES #
#################################
*/
int mirnatog = 0;
double F_monomer[2] = {0,0}; /* free energies of the two monomers */
/*
#################################
# PRIVATE VARIABLES #
#################################
*/
PRIVATE FLT_OR_DBL *expMLbase=NULL;
PRIVATE FLT_OR_DBL *q=NULL, *qb=NULL, *qm=NULL, *qm1=NULL, *qqm=NULL, *qqm1=NULL, *qq=NULL, *qq1=NULL;
PRIVATE FLT_OR_DBL *prml=NULL, *prm_l=NULL, *prm_l1=NULL, *q1k=NULL, *qln=NULL, *probs=NULL;
PRIVATE FLT_OR_DBL *scale=NULL;
PRIVATE pf_paramT *pf_params = NULL;
PRIVATE char *ptype=NULL; /* precomputed array of pair types */
PRIVATE int *jindx=NULL;
PRIVATE int *my_iindx=NULL;
PRIVATE int init_length; /* length in last call to init_pf_fold() */
PRIVATE int do_bppm = 1; /* do backtracking per default */
PRIVATE short *S=NULL, *S1=NULL;
PRIVATE char *pstruc=NULL;
PRIVATE char *sequence=NULL;
PRIVATE double alpha = 1.0;
PRIVATE int struct_constrained = 0;
#ifdef _OPENMP
/* NOTE: all variables are assumed to be uninitialized if they are declared as threadprivate
*/
#pragma omp threadprivate(expMLbase, q, qb, qm, qm1, qqm, qqm1, qq, qq1, prml, prm_l, prm_l1, q1k, qln,\
scale, pf_params, ptype, jindx, my_iindx, init_length, S, S1, pstruc, sequence, probs, do_bppm, alpha, struct_constrained)
#endif
/*
#################################
# PRIVATE FUNCTION DECLARATIONS #
#################################
*/
PRIVATE void init_partfunc_co(int length, pf_paramT *parameters);
PRIVATE void pf_co(const char *sequence);
PRIVATE void pf_co_bppm(const char *sequence, char *structure);
PRIVATE double *Newton_Conc(double ZAB, double ZAA, double ZBB, double concA, double concB,double* ConcVec);
PRIVATE void scale_pf_params(unsigned int length, pf_paramT *parameters);
PRIVATE void get_arrays(unsigned int length);
PRIVATE void make_ptypes(const short *S, const char *structure);
PRIVATE void backtrack(int i, int j);
/*
#################################
# BEGIN OF FUNCTION DEFINITIONS #
#################################
*/
PRIVATE void init_partfunc_co(int length, pf_paramT *parameters){
if (length<1) nrerror("init_pf_fold: length must be greater 0");
#ifdef _OPENMP
/* Explicitly turn off dynamic threads */
omp_set_dynamic(0);
free_co_pf_arrays(); /* free previous allocation */
#else
if (init_length>0) free_co_pf_arrays(); /* free previous allocation */
#endif
#ifdef SUN4
nonstandard_arithmetic();
#else
#ifdef HP9
fpsetfastmode(1);
#endif
#endif
make_pair_matrix();
get_arrays((unsigned) length);
scale_pf_params((unsigned) length, parameters);
init_length = length;
}
PRIVATE void get_arrays(unsigned int length){
unsigned int size;
if((length +1) >= (unsigned int)sqrt((double)INT_MAX))
nrerror("get_arrays@part_func_co.c: sequence length exceeds addressable range");
size = sizeof(FLT_OR_DBL) * ((length+1)*(length+2)/2);
q = (FLT_OR_DBL *) space(size);
qb = (FLT_OR_DBL *) space(size);
qm = (FLT_OR_DBL *) space(size);
probs = (FLT_OR_DBL *) space(size);
qm1 = (FLT_OR_DBL *) space(size);
q1k = (FLT_OR_DBL *) space(sizeof(FLT_OR_DBL)*(length+1));
qln = (FLT_OR_DBL *) space(sizeof(FLT_OR_DBL)*(length+2));
qq = (FLT_OR_DBL *) space(sizeof(FLT_OR_DBL)*(length+2));
qq1 = (FLT_OR_DBL *) space(sizeof(FLT_OR_DBL)*(length+2));
qqm = (FLT_OR_DBL *) space(sizeof(FLT_OR_DBL)*(length+2));
qqm1 = (FLT_OR_DBL *) space(sizeof(FLT_OR_DBL)*(length+2));
prm_l = (FLT_OR_DBL *) space(sizeof(FLT_OR_DBL)*(length+2));
prm_l1 = (FLT_OR_DBL *) space(sizeof(FLT_OR_DBL)*(length+2));
prml = (FLT_OR_DBL *) space(sizeof(FLT_OR_DBL)*(length+2));
expMLbase = (FLT_OR_DBL *) space(sizeof(FLT_OR_DBL)*(length+1));
scale = (FLT_OR_DBL *) space(sizeof(FLT_OR_DBL)*(length+1));
ptype = (char *) space(sizeof(char)*((length+1)*(length+2)/2));
my_iindx = get_iindx(length);
iindx = get_iindx(length); /* for backward compatibility and Perl wrapper */
jindx = get_indx(length);
}
PUBLIC void free_co_pf_arrays(void){
if(q) free(q);
if(qb) free(qb);
if(qm) free(qm);
if(qm1) free(qm1);
if(ptype) free(ptype);
if(qq) free(qq);
if(qq1) free(qq1);
if(qqm) free(qqm);
if(qqm1) free(qqm1);
if(q1k) free(q1k);
if(qln) free(qln);
if(prm_l) free(prm_l);
if(prm_l1) free(prm_l1);
if(prml) free(prml);
if(probs) free(probs);
if(expMLbase) free(expMLbase);
if(scale) free(scale);
if(my_iindx) free(my_iindx);
if(iindx) free(iindx); /* for backward compatibility and Perl wrapper */
if(jindx) free(jindx);
if(S) free(S);
if(S1) free(S1);
init_length=0;
q = qb = qm = qm1 = qq = qq1 = qqm = qqm1 = q1k = qln = prm_l = prm_l1 = prml = expMLbase = scale = probs = NULL;
ptype = NULL;
S = S1 = NULL;
my_iindx = jindx = iindx = NULL;
#ifdef SUN4
standard_arithmetic();
#else
#ifdef HP9
fpsetfastmode(0);
#endif
#endif
}
/*-----------------------------------------------------------------*/
PUBLIC cofoldF co_pf_fold(char *sequence, char *structure){
return co_pf_fold_par(sequence, structure, NULL, do_backtrack, fold_constrained);
}
PUBLIC cofoldF co_pf_fold_par(char *sequence,
char *structure,
pf_paramT *parameters,
int calculate_bppm,
int is_constrained){
int n;
FLT_OR_DBL Q;
cofoldF X;
double free_energy;
n = (int) strlen(sequence);
do_bppm = calculate_bppm;
struct_constrained = is_constrained;
#ifdef _OPENMP
/* always init everything since all global static variables are uninitialized when entering a thread */
init_partfunc_co(n, parameters);
#else
if(parameters) init_partfunc_co(n, parameters);
else if (n > init_length) init_partfunc_co(n, parameters);
else if (fabs(pf_params->temperature - temperature)>1e-6) update_co_pf_params_par(n, parameters);
#endif
/* printf("mirnatog=%d\n",mirnatog); */
if(S) free(S);
S = encode_sequence(sequence, 0);
if(S1) free(S1);
S1 = encode_sequence(sequence, 1);
make_ptypes(S, structure);
pf_co(sequence);
if (backtrack_type=='C') Q = qb[my_iindx[1]-n];
else if (backtrack_type=='M') Q = qm[my_iindx[1]-n];
else Q = q[my_iindx[1]-n];
/* ensemble free energy in Kcal/mol */
if (Q<=FLT_MIN) fprintf(stderr, "pf_scale too large\n");
free_energy = (-log(Q)-n*log(pf_params->pf_scale))*pf_params->kT/1000.0;
/* in case we abort because of floating point errors */
if (n>1600) fprintf(stderr, "free energy = %8.2f\n", free_energy);
/*probability of molecules being bound together*/
/*Computation of "real" Partition function*/
/*Need that for concentrations*/
if (cut_point>0){
double kT, pbound, QAB, QToT, Qzero;
kT = pf_params->kT/1000.0;
Qzero=q[my_iindx[1]-n];
QAB=(q[my_iindx[1]-n]-q[my_iindx[1]-(cut_point-1)]*q[my_iindx[cut_point]-n])*pf_params->expDuplexInit;
/*correction for symmetry*/
if((n-(cut_point-1)*2)==0) {
if ((strncmp(sequence, sequence+cut_point-1, cut_point-1))==0) {
QAB/=2;
}}
QToT=q[my_iindx[1]-(cut_point-1)]*q[my_iindx[cut_point]-n]+QAB;
pbound=1-(q[my_iindx[1]-(cut_point-1)]*q[my_iindx[cut_point]-n]/QToT);
X.FAB = -kT*(log(QToT)+n*log(pf_params->pf_scale));
X.F0AB = -kT*(log(Qzero)+n*log(pf_params->pf_scale));
X.FcAB = (QAB>1e-17) ? -kT*(log(QAB)+n*log(pf_params->pf_scale)) : 999;
X.FA = -kT*(log(q[my_iindx[1]-(cut_point-1)]) + (cut_point-1)*log(pf_params->pf_scale));
X.FB = -kT*(log(q[my_iindx[cut_point]-n]) + (n-cut_point+1)*log(pf_params->pf_scale));
/* printf("QAB=%.9f\tQtot=%.9f\n",QAB/scale[n],QToT/scale[n]);*/
}
else {
X.FA = X.FB = X.FAB = X.F0AB = free_energy;
X.FcAB = 0;
}
/* backtracking to construct binding probabilities of pairs*/
if(do_bppm){
pf_co_bppm(sequence, structure);
/*
* Backward compatibility:
* This block may be removed if deprecated functions
* relying on the global variable "pr" vanish from within the package!
*/
pr = probs;
/*
{
if(pr) free(pr);
pr = (FLT_OR_DBL *) space(sizeof(FLT_OR_DBL) * ((n+1)*(n+2)/2));
memcpy(pr, probs, sizeof(FLT_OR_DBL) * ((n+1)*(n+2)/2));
}
*/
}
return X;
}
/* forward recursion of pf cofolding */
PRIVATE void pf_co(const char *sequence){
int n, i,j,k,l, ij, u,u1,ii, type, type_2, tt;
FLT_OR_DBL temp, Qmax=0;
FLT_OR_DBL qbt1, *tmp;
FLT_OR_DBL expMLclosing;
double max_real;
int noGUclosure = pf_params->model_details.noGUclosure;
max_real = (sizeof(FLT_OR_DBL) == sizeof(float)) ? FLT_MAX : DBL_MAX;
n = (int) strlen(sequence);
expMLclosing = pf_params->expMLclosing;
/*array initialization ; qb,qm,q
qb,qm,q (i,j) are stored as ((n+1-i)*(n-i) div 2 + n+1-j */
/* for (d=0; d<=TURN; d++) */
for (i=1; i<=n/*-d*/; i++) {
ij = my_iindx[i]-i;
q[ij]=scale[1];
qb[ij]=qm[ij]=0.0;
}
for (i=0; i<=n; i++)
qq[i]=qq1[i]=qqm[i]=qqm1[i]=prm_l[i]=prm_l1[i]=prml[i]=0;
for (j=TURN+2;j<=n; j++) {
for (i=j-TURN-1; i>=1; i--) {
/* construction of partition function of segment i,j*/
/*firstly that given i bound to j : qb(i,j) */
u = j-i-1; ij = my_iindx[i]-j;
type = ptype[ij];
qbt1=0;
if (type!=0) {
/*hairpin contribution*/
if SAME_STRAND(i,j){
if (((type==3)||(type==4))&&noGUclosure) qbt1 = 0;
else
qbt1 = exp_E_Hairpin(u, type, S1[i+1], S1[j-1], sequence+i-1, pf_params)*scale[u+2];
}
/* interior loops with interior pair k,l */
for (k=i+1; k<=MIN2(i+MAXLOOP+1,j-TURN-2); k++) {
u1 = k-i-1;
for (l=MAX2(k+TURN+1,j-1-MAXLOOP+u1); l<j; l++) {
if ((SAME_STRAND(i,k))&&(SAME_STRAND(l,j))){
type_2 = ptype[my_iindx[k]-l];
if (type_2) {
type_2 = rtype[type_2];
qbt1 += qb[my_iindx[k]-l] *
exp_E_IntLoop(u1, j-l-1, type, type_2,
S1[i+1], S1[j-1], S1[k-1], S1[l+1], pf_params)*scale[u1+j-l+1];
}
}
}
}
/*multiple stem loop contribution*/
ii = my_iindx[i+1]; /* ii-k=[i+1,k-1] */
temp = 0.0;
if (SAME_STRAND(i,i+1) && SAME_STRAND(j-1,j)) {
for (k=i+2; k<=j-1; k++) {
if (SAME_STRAND(k-1,k))
temp += qm[ii-(k-1)]*qqm1[k];
}
tt = rtype[type];
temp*=exp_E_MLstem(tt, S1[j-1], S1[i+1], pf_params)*scale[2];
temp*=expMLclosing;
qbt1 += temp;
}
/*qc contribution*/
temp=0.0;
if (!SAME_STRAND(i,j)){
tt = rtype[type];
temp=q[my_iindx[i+1]-(cut_point-1)]*q[my_iindx[cut_point]-(j-1)];
if ((j==cut_point)&&(i==cut_point-1)) temp=scale[2];
else if (i==cut_point-1) temp=q[my_iindx[cut_point]-(j-1)]*scale[1];
else if (j==cut_point) temp=q[my_iindx[i+1]-(cut_point-1)]*scale[1];
if (j>cut_point) temp*=scale[1];
if (i<cut_point-1) temp*=scale[1];
temp *= exp_E_ExtLoop(tt, SAME_STRAND(j-1,j) ? S1[j-1] : -1, SAME_STRAND(i,i+1) ? S1[i+1] : -1, pf_params);
qbt1+=temp;
}
qb[ij] = qbt1;
} /* end if (type!=0) */
else qb[ij] = 0.0;
/* construction of qqm matrix containing final stem
contributions to multiple loop partition function
from segment i,j */
if (SAME_STRAND(j-1,j)) {
qqm[i] = qqm1[i]*expMLbase[1];
}
else qqm[i]=0;
if (type&&SAME_STRAND(i-1,i)&&SAME_STRAND(j,j+1)) {
qbt1 = qb[ij];
qbt1 *= exp_E_MLstem(type, (i>1) ? S1[i-1] : -1, (j<n) ? S1[j+1] : -1, pf_params);
qqm[i] += qbt1;
}
if (qm1) qm1[jindx[j]+i] = qqm[i]; /* for stochastic backtracking */
/*construction of qm matrix containing multiple loop
partition function contributions from segment i,j */
temp = 0.0;
ii = my_iindx[i]; /* ii-k=[i,k] */
for (k=i+1; k<=j; k++) {
if (SAME_STRAND(k-1,k)) temp += (qm[ii-(k-1)])*qqm[k];
if (SAME_STRAND(i,k)) temp += expMLbase[k-i]*qqm[k];
}
qm[ij] = (temp + qqm[i]);
/*auxiliary matrix qq for cubic order q calculation below */
qbt1 = qb[ij];
if (type) {
qbt1 *= exp_E_ExtLoop(type, ((i>1)&&(SAME_STRAND(i-1,i))) ? S1[i-1] : -1, ((j<n)&&(SAME_STRAND(j,j+1))) ? S1[j+1] : -1, pf_params);
}
qq[i] = qq1[i]*scale[1] + qbt1;
/*construction of partition function for segment i,j */
temp = 1.0*scale[1+j-i] + qq[i];
for (k=i; k<=j-1; k++) temp += q[ii-k]*qq[k+1];
q[ij] = temp;
if (temp>Qmax) {
Qmax = temp;
if (Qmax>max_real/10.)
fprintf(stderr, "Q close to overflow: %d %d %g\n", i,j,temp);
}
if (temp>=max_real) {
PRIVATE char msg[128];
snprintf(msg, 127, "overflow in co_pf_fold while calculating q[%d,%d]\n"
"use larger pf_scale", i,j);
nrerror(msg);
}
}
tmp = qq1; qq1 =qq; qq =tmp;
tmp = qqm1; qqm1=qqm; qqm=tmp;
}
}
/* backward recursion of pf cofolding */
PRIVATE void pf_co_bppm(const char *sequence, char *structure){
int n, i,j,k,l, ij, kl, ii, ll, type, type_2, tt, ov=0;
FLT_OR_DBL temp, Qmax=0, prm_MLb;
FLT_OR_DBL prmt,prmt1;
FLT_OR_DBL *tmp;
FLT_OR_DBL expMLclosing;
double max_real;
max_real = (sizeof(FLT_OR_DBL) == sizeof(float)) ? FLT_MAX : DBL_MAX;
n = (int) strlen(sequence);
expMLclosing = pf_params->expMLclosing;
/* backtracking to construct binding probabilities of pairs*/
if ((S != NULL) && (S1 != NULL)) {
FLT_OR_DBL *Qlout, *Qrout;
Qmax=0;
Qrout=(FLT_OR_DBL *)space(sizeof(FLT_OR_DBL) * (n+2));
Qlout=(FLT_OR_DBL *)space(sizeof(FLT_OR_DBL) * (cut_point+2));
for (k=1; k<=n; k++) {
q1k[k] = q[my_iindx[1] - k];
qln[k] = q[my_iindx[k] -n];
}
q1k[0] = 1.0;
qln[n+1] = 1.0;
/* pr = q; / * recycling */
/* 1. exterior pair i,j and initialization of pr array */
for (i=1; i<=n; i++) {
for (j=i; j<=MIN2(i+TURN,n); j++) probs[my_iindx[i]-j] = 0;
for (j=i+TURN+1; j<=n; j++) {
ij = my_iindx[i]-j;
type = ptype[ij];
if (type&&(qb[ij]>0.)) {
probs[ij] = q1k[i-1]*qln[j+1]/q1k[n];
probs[ij] *= exp_E_ExtLoop(type, ((i>1)&&(SAME_STRAND(i-1,i))) ? S1[i-1] : -1, ((j<n)&&(SAME_STRAND(j,j+1))) ? S1[j+1] : -1, pf_params);
} else
probs[ij] = 0;
}
}
for (l=n; l>TURN+1; l--) {
/* 2. bonding k,l as substem of 2:loop enclosed by i,j */
for (k=1; k<l-TURN; k++) {
kl = my_iindx[k]-l;
type_2 = ptype[kl]; type_2 = rtype[type_2];
if (qb[kl]==0) continue;
for (i=MAX2(1,k-MAXLOOP-1); i<=k-1; i++)
for (j=l+1; j<=MIN2(l+ MAXLOOP -k+i+2,n); j++) {
if ((SAME_STRAND(i,k))&&(SAME_STRAND(l,j))){
ij = my_iindx[i] - j;
type = ptype[ij];
if ((probs[ij]>0)) {
probs[kl] += probs[ij]*exp_E_IntLoop(k-i-1, j-l-1, type, type_2,
S1[i+1], S1[j-1], S1[k-1], S1[l+1], pf_params)*scale[k-i+j-l];
}
}
}
}
/* 3. bonding k,l as substem of multi-loop enclosed by i,j */
prm_MLb = 0.;
if ((l<n)&&(SAME_STRAND(l,l+1)))
for (k=2; k<l-TURN; k++) {
i = k-1;
prmt = prmt1 = 0.0;
ii = my_iindx[i]; /* ii-j=[i,j] */
ll = my_iindx[l+1]; /* ll-j=[l+1,j] */
tt = ptype[ii-(l+1)]; tt=rtype[tt];
if (SAME_STRAND(i,k)){
prmt1 = probs[ii-(l+1)]*expMLclosing;
prmt1 *= exp_E_MLstem(tt, S1[l], S1[i+1], pf_params);
for (j=l+2; j<=n; j++) {
if (SAME_STRAND(j-1,j)){ /*??*/
tt = ptype[ii-j]; tt = rtype[tt];
prmt += probs[ii-j]*exp_E_MLstem(tt, S1[j-1], S1[i+1], pf_params)*qm[ll-(j-1)];
}
}
}
kl = my_iindx[k]-l;
tt = ptype[kl];
prmt *= expMLclosing;
prml[ i] = prmt;
prm_l[i] = prm_l1[i]*expMLbase[1]+prmt1;
prm_MLb = prm_MLb*expMLbase[1] + prml[i];
/* same as: prm_MLb = 0;
for (i=1; i<=k-1; i++) prm_MLb += prml[i]*expMLbase[k-i-1]; */
prml[i] = prml[ i] + prm_l[i];
if (qb[kl] == 0.) continue;
temp = prm_MLb;
for (i=1;i<=k-2; i++) {
if ((SAME_STRAND(i,i+1))&&(SAME_STRAND(k-1,k))){
temp += prml[i]*qm[my_iindx[i+1] - (k-1)];
}
}
temp *= exp_E_MLstem( tt,
((k>1)&&SAME_STRAND(k-1,k)) ? S1[k-1] : -1,
((l<n)&&SAME_STRAND(l,l+1)) ? S1[l+1] : -1,
pf_params) * scale[2];
probs[kl] += temp;
if (probs[kl]>Qmax) {
Qmax = probs[kl];
if (Qmax>max_real/10.)
fprintf(stderr, "P close to overflow: %d %d %g %g\n",
i, j, probs[kl], qb[kl]);
}
if (probs[kl]>=max_real) {
ov++;
probs[kl]=FLT_MAX;
}
} /* end for (k=..) multloop*/
else /* set prm_l to 0 to get prm_l1 to be 0 */
for (i=0; i<=n; i++) prm_l[i]=0;
tmp = prm_l1; prm_l1=prm_l; prm_l=tmp;
/*computation of .(..(...)..&..). type features?*/
if (cut_point<=0) continue; /* no .(..(...)..&..). type features*/
if ((l==n)||(l<=2)) continue; /* no .(..(...)..&..). type features*/
/*new version with O(n^3)??*/
if (l>cut_point) {
if (l<n) {
int t,kt;
for (t=n; t>l; t--) {
for (k=1; k<cut_point; k++) {
kt=my_iindx[k]-t;
type=rtype[ptype[kt]];
temp = probs[kt] * exp_E_ExtLoop(type, S1[t-1], (SAME_STRAND(k,k+1)) ? S1[k+1] : -1, pf_params) * scale[2];
if (l+1<t) temp*=q[my_iindx[l+1]-(t-1)];
if (SAME_STRAND(k,k+1)) temp*=q[my_iindx[k+1]-(cut_point-1)];
Qrout[l]+=temp;
}
}
}
for (k=l-1; k>=cut_point; k--) {
if (qb[my_iindx[k]-l]) {
kl=my_iindx[k]-l;
type=ptype[kl];
temp = Qrout[l];
temp *= exp_E_ExtLoop(type, (k>cut_point) ? S1[k-1] : -1, (l < n) ? S1[l+1] : -1, pf_params);
if (k>cut_point) temp*=q[my_iindx[cut_point]-(k-1)];
probs[kl]+=temp;
}
}
}
else if (l==cut_point ) {
int t, sk,s;
for (t=2; t<cut_point;t++) {
for (s=1; s<t; s++) {
for (k=cut_point; k<=n; k++) {
sk=my_iindx[s]-k;
if (qb[sk]) {
type=rtype[ptype[sk]];
temp=probs[sk]*exp_E_ExtLoop(type, (SAME_STRAND(k-1,k)) ? S1[k-1] : -1, S1[s+1], pf_params)*scale[2];
if (s+1<t) temp*=q[my_iindx[s+1]-(t-1)];
if (SAME_STRAND(k-1,k)) temp*=q[my_iindx[cut_point]-(k-1)];
Qlout[t]+=temp;
}
}
}
}
}
else if (l<cut_point) {
for (k=1; k<l; k++) {
if (qb[my_iindx[k]-l]) {
type=ptype[my_iindx[k]-l];
temp=Qlout[k];
temp *= exp_E_ExtLoop(type, (k>1) ? S1[k-1] : -1, (l<(cut_point-1)) ? S1[l+1] : -1, pf_params);
if (l+1<cut_point) temp*=q[my_iindx[l+1]-(cut_point-1)];
probs[my_iindx[k]-l]+=temp;
}
}
}
} /* end for (l=..) */
free(Qlout);
free(Qrout);
for (i=1; i<=n; i++)
for (j=i+TURN+1; j<=n; j++) {
ij = my_iindx[i]-j;
probs[ij] *= qb[ij];
}
if (structure!=NULL)
bppm_to_structure(structure, probs, n);
} /* end if (do_backtrack)*/
if (ov>0) fprintf(stderr, "%d overflows occurred while backtracking;\n"
"you might try a smaller pf_scale than %g\n",
ov, pf_params->pf_scale);
}
PRIVATE void scale_pf_params(unsigned int length, pf_paramT *parameters){
unsigned int i;
double kT, scaling_factor;
if(pf_params) free(pf_params);
if(parameters){
pf_params = get_boltzmann_factor_copy(parameters);
} else {
model_detailsT md;
set_model_details(&md);
pf_params = get_boltzmann_factors(temperature, alpha, md, pf_scale);
}
scaling_factor = pf_params->pf_scale;
kT = pf_params->kT; /* kT in cal/mol */
/* scaling factors (to avoid overflows) */
if (scaling_factor == -1) { /* mean energy for random sequences: 184.3*length cal */
scaling_factor = exp(-(-185+(pf_params->temperature-37.)*7.27)/kT);
if (scaling_factor<1) scaling_factor=1;
pf_params->pf_scale = scaling_factor;
}
scale[0] = 1.;
scale[1] = 1./scaling_factor;
expMLbase[0] = 1;
expMLbase[1] = pf_params->expMLbase/scaling_factor;
for (i=2; i<=length; i++) {
scale[i] = scale[i/2]*scale[i-(i/2)];
expMLbase[i] = pow(pf_params->expMLbase, (double)i) * scale[i];
}
}
/*----------------------------------------------------------------------*/
/*----------------------------------------------------------------------*/
/*---------------------------------------------------------------------------*/
PUBLIC void update_co_pf_params(int length){
update_co_pf_params_par(length, NULL);
}
PUBLIC void update_co_pf_params_par(int length, pf_paramT *parameters){
make_pair_matrix();
scale_pf_params((unsigned) length, parameters);
}
/*---------------------------------------------------------------------------*/
PRIVATE void make_ptypes(const short *S, const char *structure) {
int n,i,j,k,l;
int noLP = pf_params->model_details.noLP;
n=S[0];
for (k=1; k<=n-TURN-1; k++)
for (l=1; l<=2; l++) {
int type,ntype=0,otype=0;
i=k; j = i+TURN+l;
if (j>n) continue;
type = pair[S[i]][S[j]];
while ((i>=1)&&(j<=n)) {
if ((i>1)&&(j<n)) ntype = pair[S[i-1]][S[j+1]];
if (noLP && (!otype) && (!ntype))
type = 0; /* i.j can only form isolated pairs */
qb[my_iindx[i]-j] = 0.;
ptype[my_iindx[i]-j] = (char) type;
otype = type;
type = ntype;
i--; j++;
}
}
if (struct_constrained&&(structure!=NULL)) {
constrain_ptypes(structure, (unsigned int)n, ptype, NULL, TURN, 1);
for(j=1; j<=n; j++) {
switch (structure[j-1]) {
case 'l': /*only intramolecular basepairing*/
if (j<cut_point) for (l=cut_point; l<=n; l++) ptype[my_iindx[j]-l] = 0;
else for (l=1; l<cut_point; l++) ptype[my_iindx[l]-j] =0;
break;
case 'e': /*only intermolecular bp*/
if (j<cut_point) {
for (l=1; l<j; l++) ptype[my_iindx[l]-j] =0;
for (l=j+1; l<cut_point; l++) ptype[my_iindx[j]-l] = 0;
}
else {
for (l=cut_point; l<j; l++) ptype[my_iindx[l]-j] =0;
for (l=j+1; l<=n; l++) ptype[my_iindx[j]-l] = 0;
}
break;
}
}
}
if (mirnatog==1) { /*microRNA toggle: no intramolec. bp in 2. molec*/
for (j=cut_point; j<n; j++) {
for (l=j+1; l<=n; l++) {
ptype[my_iindx[j]-l] = 0;
}
}
}
}
/*
stochastic backtracking in pf_fold arrays
returns random structure S with Boltzman probabilty
p(S) = exp(-E(S)/kT)/Z
*/
PRIVATE void backtrack_qm1(int i,int j) {
/* i is paired to l, i<l<j; backtrack in qm1 to find l */
int ii, l, type;
double qt, r;
r = urn() * qm1[jindx[j]+i];
ii = my_iindx[i];
for (qt=0., l=i+TURN+1; l<=j; l++) {
type = ptype[ii-l];
if (type)
qt += qb[ii-l]*exp_E_MLstem(type, S1[i-1], S1[l+1], pf_params) * expMLbase[j-l];
if (qt>=r) break;
}
if (l>j) nrerror("backtrack failed in qm1");
backtrack(i,l);
}
PRIVATE void backtrack(int i, int j) {
int noGUclosure = pf_params->model_details.noGUclosure;
do {
double r, qbt1;
int k, l, type, u, u1;
pstruc[i-1] = '('; pstruc[j-1] = ')';
r = urn() * qb[my_iindx[i]-j];
type = ptype[my_iindx[i]-j];
u = j-i-1;
/*hairpin contribution*/
if (((type==3)||(type==4))&&noGUclosure) qbt1 = 0;
else
qbt1 = exp_E_Hairpin(u, type, S1[i+1], S1[j-1], sequence+i-1, pf_params)*scale[u+2];
if (qbt1>r) return; /* found the hairpin we're done */
for (k=i+1; k<=MIN2(i+MAXLOOP+1,j-TURN-2); k++) {
u1 = k-i-1;
for (l=MAX2(k+TURN+1,j-1-MAXLOOP+u1); l<j; l++) {
int type_2;
type_2 = ptype[my_iindx[k]-l];
if (type_2) {
type_2 = rtype[type_2];
qbt1 += qb[my_iindx[k]-l] *
exp_E_IntLoop(u1, j-l-1, type, type_2,
S1[i+1], S1[j-1], S1[k-1], S1[l+1], pf_params)*scale[u1+j-l+1];
}
if (qbt1 > r) break;
}
if (qbt1 > r) break;
}
if (l<j) {
i=k; j=l;
}
else break;
} while (1);
/* backtrack in multi-loop */
{
double r, qt;
int k, ii, jj;
i++; j--;
/* find the first split index */
ii = my_iindx[i]; /* ii-j=[i,j] */
jj = jindx[j]; /* jj+i=[j,i] */
for (qt=0., k=i+1; k<j; k++) qt += qm[ii-(k-1)]*qm1[jj+k];
r = urn() * qt;
for (qt=0., k=i+1; k<j; k++) {
qt += qm[ii-(k-1)]*qm1[jj+k];
if (qt>=r) break;
}
if (k>=j) nrerror("backtrack failed, can't find split index ");
backtrack_qm1(k, j);
j = k-1;
while (j>i) {
/* now backtrack [i ... j] in qm[] */
jj = jindx[j];
ii = my_iindx[i];
r = urn() * qm[ii - j];
qt = qm1[jj+i]; k=i;
if (qt<r)
for (k=i+1; k<=j; k++) {
qt += (qm[ii-(k-1)]+expMLbase[k-i])*qm1[jj+k];
if (qt >= r) break;
}
if (k>j) nrerror("backtrack failed in qm");
backtrack_qm1(k,j);
if (k<i+TURN) break; /* no more pairs */
r = urn() * (qm[ii-(k-1)] + expMLbase[k-i]);
if (expMLbase[k-i] >= r) break; /* no more pairs */
j = k-1;
}
}
}
PUBLIC void compute_probabilities(double FAB, double FA,double FB,
struct plist *prAB,
struct plist *prA, struct plist *prB,
int Alength) {
/*computes binding probabilities and dimer free energies*/
int i, j;
double pAB;
double mykT;
struct plist *lp1, *lp2;
int offset;
mykT=pf_params->kT/1000.;
/* pair probabilities in pr are relative to the null model (without DuplexInit) */
/*Compute probabilities pAB, pAA, pBB*/
pAB=1.-exp((1/mykT)*(FAB-FA-FB));
/* compute pair probabilities given that it is a dimer */
/* AB dimer */
offset=0;
lp2=prA;
if (pAB>0)
for (lp1=prAB; lp1->j>0; lp1++) {
float pp=0;
i=lp1->i; j=lp1->j;
while (offset+lp2->i < i && lp2->i>0) lp2++;
if (offset+lp2->i == i)
while ((offset+lp2->j) < j && (lp2->j>0)) lp2++;
if (lp2->j == 0) {lp2=prB; offset=Alength;}/* jump to next list */
if ((offset+lp2->i==i) && (offset+lp2->j ==j)) {
pp = lp2->p;
lp2++;
}
lp1->p=(lp1->p-(1-pAB)*pp)/pAB;
if(lp1->p < 0.){
warn_user("part_func_co: numeric instability detected, probability below zero!");
lp1->p = 0.;
}
}
return;
}
PRIVATE double *Newton_Conc(double KAB, double KAA, double KBB, double concA, double concB,double* ConcVec) {
double TOL, EPS, xn, yn, det, cA, cB;
int i=0;
/*Newton iteration for computing concentrations*/
cA=concA;
cB=concB;
TOL=1e-6; /*Tolerance for convergence*/
ConcVec=(double*)space(5*sizeof(double)); /* holds concentrations */
do {
/* det = (4.0 * KAA * cA + KAB *cB + 1.0) * (4.0 * KBB * cB + KAB *cA + 1.0) - (KAB *cB) * (KAB *cA); */
det = 1 + 16. *KAA*KBB*cA*cB + KAB*(cA+cB) + 4.*KAA*cA + 4.*KBB*cB + 4.*KAB*(KBB*cB*cB + KAA*cA*cA);
/* xn = ( (2.0 * KBB * cB*cB + KAB *cA *cB + cB - concB) * (KAB *cA) -
(2.0 * KAA * cA*cA + KAB *cA *cB + cA - concA) * (4.0 * KBB * cB + KAB *cA + 1.0) ) /det; */
xn = ( (2.0 * KBB * cB*cB + cB - concB) * (KAB *cA) - KAB*cA*cB*(4. * KBB*cB + 1.) -
(2.0 * KAA * cA*cA + cA - concA) * (4.0 * KBB * cB + KAB *cA + 1.0) ) /det;
/* yn = ( (2.0 * KAA * cA*cA + KAB *cA *cB + cA - concA) * (KAB *cB) -
(2.0 * KBB * cB*cB + KAB *cA *cB + cB - concB) * (4.0 * KAA * cA + KAB *cB + 1.0) ) /det; */
yn = ( (2.0 * KAA * cA*cA + cA - concA) * (KAB *cB) - KAB*cA*cB*(4. * KAA*cA + 1.) -
(2.0 * KBB * cB*cB + cB - concB) * (4.0 * KAA * cA + KAB *cB + 1.0) ) /det;
EPS = fabs(xn/cA) + fabs(yn/cB);
cA += xn;
cB += yn;
i++;
if (i>10000) {
fprintf(stderr, "Newton did not converge after %d steps!!\n",i);
break;
}
} while(EPS>TOL);
ConcVec[0]= cA*cB*KAB ;/*AB concentration*/
ConcVec[1]= cA*cA*KAA ;/*AA concentration*/
ConcVec[2]= cB*cB*KBB ;/*BB concentration*/
ConcVec[3]= cA; /* A concentration*/
ConcVec[4]= cB; /* B concentration*/
return ConcVec;
}
PUBLIC struct ConcEnt *get_concentrations(double FcAB, double FcAA, double FcBB, double FEA, double FEB, double *startconc)
{
/*takes an array of start concentrations, computes equilibrium concentrations of dimers, monomers, returns array of concentrations in strucutre ConcEnt*/
double *ConcVec;
int i;
struct ConcEnt *Concentration;
double KAA, KAB, KBB, kT;
kT=pf_params->kT/1000.;
Concentration=(struct ConcEnt *)space(20*sizeof(struct ConcEnt));
/* Compute equilibrium constants */
/* again note the input free energies are not from the null model (without DuplexInit) */
KAA = exp(( 2.0 * FEA - FcAA)/kT);
KBB = exp(( 2.0 * FEB - FcBB)/kT);
KAB = exp(( FEA + FEB - FcAB)/kT);
/* printf("Kaa..%g %g %g\n", KAA, KBB, KAB); */
for (i=0; ((startconc[i]!=0)||(startconc[i+1]!=0));i+=2) {
ConcVec=Newton_Conc(KAB, KAA, KBB, startconc[i], startconc[i+1], ConcVec);
Concentration[i/2].A0=startconc[i];
Concentration[i/2].B0=startconc[i+1];
Concentration[i/2].ABc=ConcVec[0];
Concentration[i/2].AAc=ConcVec[1];
Concentration[i/2].BBc=ConcVec[2];
Concentration[i/2].Ac=ConcVec[3];
Concentration[i/2].Bc=ConcVec[4];
if (!(((i+2)/2)%20)) {
Concentration=(struct ConcEnt *)xrealloc(Concentration,((i+2)/2+20)*sizeof(struct ConcEnt));
}
free(ConcVec);
}
return Concentration;
}
PUBLIC FLT_OR_DBL *export_co_bppm(void){
return probs;
}
/*###########################################*/
/*# deprecated functions below #*/
/*###########################################*/
PUBLIC struct plist *get_plist(struct plist *pl, int length, double cut_off) {
int i, j,n, count;
/*get pair probibilities out of pr array*/
count=0;
n=2;
for (i=1; i<length; i++) {
for (j=i+1; j<=length; j++) {
if (pr[my_iindx[i]-j]<cut_off) continue;
if (count==n*length-1) {
n*=2;
pl=(struct plist *)xrealloc(pl,n*length*sizeof(struct plist));
}
pl[count].i=i;
pl[count].j=j;
pl[count++].p=pr[my_iindx[i]-j];
/* printf("gpl: %2d %2d %.9f\n",i,j,pr[my_iindx[i]-j]);*/
}
}
pl[count].i=0;
pl[count].j=0; /*->??*/
pl[count++].p=0.;
pl=(struct plist *)xrealloc(pl,(count)*sizeof(struct plist));
return pl;
}
PUBLIC void init_co_pf_fold(int length){ /* DO NOTHING */ }