/*
* BioJava development code
*
* This code may be freely distributed and modified under the
* terms of the GNU Lesser General Public Licence. This should
* be distributed with the code. If you do not have a copy,
* see:
*
* http://www.gnu.org/copyleft/lesser.html
*
* Copyright for this code is held jointly by the individual
* authors. These should be listed in @author doc comments.
*
* For more information on the BioJava project and its aims,
* or to join the biojava-l mailing list, visit the home page
* at:
*
* http://www.biojava.org/
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*/
package org.biojava.nbio.structure.io;
import org.biojava.nbio.alignment.Alignments;
import org.biojava.nbio.alignment.Alignments.PairwiseSequenceAlignerType;
import org.biojava.nbio.alignment.SimpleGapPenalty;
import org.biojava.nbio.core.alignment.matrices.SubstitutionMatrixHelper;
import org.biojava.nbio.alignment.template.GapPenalty;
import org.biojava.nbio.alignment.template.PairwiseSequenceAligner;
import org.biojava.nbio.core.alignment.template.SequencePair;
import org.biojava.nbio.core.alignment.template.SubstitutionMatrix;
import org.biojava.nbio.core.exceptions.CompoundNotFoundException;
import org.biojava.nbio.core.sequence.DNASequence;
import org.biojava.nbio.core.sequence.ProteinSequence;
import org.biojava.nbio.core.sequence.RNASequence;
import org.biojava.nbio.core.sequence.compound.AminoAcidCompound;
import org.biojava.nbio.core.sequence.compound.NucleotideCompound;
import org.biojava.nbio.structure.*;
import org.slf4j.Logger;
import org.slf4j.LoggerFactory;
import java.util.ArrayList;
import java.util.Collections;
import java.util.Comparator;
import java.util.HashMap;
import java.util.List;
import java.util.Map;
import java.util.Set;
import java.util.TreeMap;
import java.util.TreeSet;
/**
* Heuristical finding of Entities (called Compounds in legacy PDB format)
* in a given Structure. Entities are the groups of sequence identical NCS-related polymer chains
* in the Structure.
*
* This is related to {@link SeqRes2AtomAligner} but it is intended for raw PDB/mmCIF files where
* possibly no SEQRES is given.
*
* @author Jose Duarte
*/
public class EntityFinder {
private static final Logger logger = LoggerFactory.getLogger(EntityFinder.class);
/**
* Above this ratio of mismatching residue types for same residue numbers we
* consider the 2 chains to have mismatching residue numbers and warn about it
*/
public static final double RATIO_GAPS_FOR_MISMATCH = 0.50;
/**
* Identity value for 2 chains to be considered part of same entity
*/
public static final double IDENTITY_THRESHOLD = 0.99999;
/**
* Gap coverage value (num gaps over length of sequence) for each chain of the match:
* 2 chains with more gap coverage than this value will not be considered part of the same entity
*/
public static final double GAP_COVERAGE_THRESHOLD = 0.3;
/**
* Utility method that employs some heuristics to find the {@link EntityInfo}s
* for the polymeric chains given in constructor.
* To be used in case the information is missing in PDB/mmCIF file
* @return
*/
public static List<EntityInfo> findPolyEntities(List<List<Chain>> polyModels) {
TreeMap<String,EntityInfo> chainIds2entities = findEntitiesFromAlignment(polyModels);
List<EntityInfo> entities = findUniqueEntities(chainIds2entities);
return entities;
}
/**
* Utility method to obtain a list of unique entities from the chainIds2entities map
* @return
*/
private static List<EntityInfo> findUniqueEntities(TreeMap<String,EntityInfo> chainIds2entities) {
List<EntityInfo> list = new ArrayList<EntityInfo>();
for (EntityInfo cluster:chainIds2entities.values()) {
boolean present = false;
for (EntityInfo cl:list) {
if (cl==cluster) {
present = true;
break;
}
}
if (!present) list.add(cluster);
}
return list;
}
/**
* Given all chains of all models find entities for the nonpolymers and water chains within them,
* assigning entity ids, types and descriptions to them. The result is written back to the passed entities List.
* @param nonPolyModels
* @param waterModels
* @param entities
*/
public static void createPurelyNonPolyEntities(List<List<Chain>> nonPolyModels, List<List<Chain>> waterModels, List<EntityInfo> entities) {
if (nonPolyModels.isEmpty()) return;
// let's find first the max entity id to assign entity ids to the newly found entities
int maxMolId = 0;
if (!entities.isEmpty()) {
maxMolId = Collections.max(entities, new Comparator<EntityInfo>() {
@Override
public int compare(EntityInfo o1, EntityInfo o2) {
return new Integer(o1.getMolId()).compareTo(o2.getMolId());
}
}).getMolId();
}
// we go one over the max
int molId = maxMolId + 1;
if (!nonPolyModels.get(0).isEmpty()) {
List<EntityInfo> nonPolyEntities = new ArrayList<>();
for (List<Chain> model:nonPolyModels) {
for (Chain c: model) {
// we assume there's only 1 group per non-poly chain
String molecPdbName = c.getAtomGroup(0).getPDBName();
EntityInfo nonPolyEntity = findNonPolyEntityWithDescription(molecPdbName, nonPolyEntities);
if (nonPolyEntity == null) {
nonPolyEntity = new EntityInfo();
nonPolyEntity.setDescription(molecPdbName);
nonPolyEntity.setType(EntityType.NONPOLYMER);
nonPolyEntity.setMolId(molId++);
nonPolyEntities.add(nonPolyEntity);
}
nonPolyEntity.addChain(c);
c.setEntityInfo(nonPolyEntity);
}
}
entities.addAll(nonPolyEntities);
}
if (!waterModels.get(0).isEmpty()) {
EntityInfo waterEntity = new EntityInfo();
waterEntity.setType(EntityType.WATER);
waterEntity.setDescription("water");
waterEntity.setMolId(molId);
for (List<Chain> model:waterModels) {
for (Chain waterChain:model) {
waterEntity.addChain(waterChain);
waterChain.setEntityInfo(waterEntity);
}
}
entities.add(waterEntity);
}
}
private static EntityInfo findNonPolyEntityWithDescription(String description, List<EntityInfo> nonPolyEntities) {
for (EntityInfo e:nonPolyEntities) {
if (e.getDescription().equals(description)) return e;
}
return null;
}
private static boolean areResNumbersAligned(Chain c1, Chain c2) {
boolean isC1prot = StructureTools.isProtein(c1);
boolean isC2prot = StructureTools.isProtein(c2);
// different kind of chain: we won't try to align them
if (isC1prot != isC2prot ) return false;
List<Group> c1AtomGroups = null;
if (isC1prot) {
c1AtomGroups = c1.getAtomGroups(GroupType.AMINOACID);
}
else {
c1AtomGroups = c1.getAtomGroups(GroupType.NUCLEOTIDE);
}
int countNonExisting = 0;
for (Group g1:c1AtomGroups) {
try {
Group g2 = c2.getGroupByPDB(g1.getResidueNumber());
if (!g2.getPDBName().equals(g1.getPDBName())) {
logger.debug("Mismatch of residues between chains {},{} for residue number {}: {} {}",
c1.getId(),c2.getId(),g1.getResidueNumber(), g1.getPDBName(), g2.getPDBName());
return false;
}
} catch (StructureException e) {
// the group doesn't exist (no density) in the chain, go on
countNonExisting++;
continue;
}
}
if ((double)countNonExisting/(double)c1AtomGroups.size() > RATIO_GAPS_FOR_MISMATCH) {
logger.debug("More than {} of the residues ({} out of {}) are not present in chain {} when comparing by residue numbers to chain {}.",
RATIO_GAPS_FOR_MISMATCH, countNonExisting, c1AtomGroups.size(), c2.getId(), c1.getId());
return false;
}
return true;
}
private static TreeMap<String,EntityInfo> findEntitiesFromAlignment(List<List<Chain>> polyModels) {
TreeMap<String, EntityInfo> chainIds2entities = new TreeMap<String,EntityInfo>();
if (polyModels.isEmpty()) return chainIds2entities;
Set<Integer> polyChainIndices = new TreeSet<Integer>();
for (int i=0;i<polyModels.get(0).size();i++) {
polyChainIndices.add(i);
}
int molId = 1;
outer:
for (int i:polyChainIndices) {
for (int j:polyChainIndices) {
if (j<=i) continue;
Chain c1 = polyModels.get(0).get(i);
Chain c2 = polyModels.get(0).get(j);
Map<Integer,Integer> positionIndex1 = new HashMap<Integer, Integer>();
Map<Integer,Integer> positionIndex2 = new HashMap<Integer, Integer>();
// here we use false, which means that X will be used for unknown compounds
String str1 = SeqRes2AtomAligner.getFullAtomSequence(c1.getAtomGroups(), positionIndex1, false);
String str2 = SeqRes2AtomAligner.getFullAtomSequence(c2.getAtomGroups(), positionIndex2, false);
int seq1Length = 0;
int seq2Length = 0;
SequencePair<?,?> pair = null;
if (isProteinSequence(str1) && isProteinSequence(str2)) {
ProteinSequence s1 = getProteinSequence(str1);
ProteinSequence s2 = getProteinSequence(str2);
seq1Length = s1.getLength();
seq2Length = s2.getLength();
pair = alignProtein(s1,s2);
} else if (isDNASequence(str1) && isDNASequence(str2)) {
DNASequence s1 = getDNASequence(str1);
DNASequence s2 = getDNASequence(str2);
seq1Length = s1.getLength();
seq2Length = s2.getLength();
pair = alignDNA(s1,s2);
} else if (isRNASequence(str1) && isRNASequence(str2)) {
RNASequence s1 = getRNASequence(str1);
RNASequence s2 = getRNASequence(str2);
seq1Length = s1.getLength();
seq2Length = s2.getLength();
pair = alignRNA(s1,s2);
} else {
logger.debug("Chains {},{} are either different kind of polymers or could not be recognized as protein or nucleotide polymers");
continue;
}
int numGaps = getNumGaps(pair);
int numGaps1 = getNumGapsQuery(pair);
int numGaps2 = getNumGapsTarget(pair);
int nonGaps = pair.getLength() - numGaps;
double identity = (double)pair.getNumIdenticals()/(double)nonGaps;
double gapCov1 = (double) numGaps1 / (double) seq1Length;
double gapCov2 = (double) numGaps2 / (double) seq2Length;
logger.debug("Alignment for chain pair {},{}: identity: {}, gap coverage 1: {}, gap coverage 2: {}",
c1.getId(), c2.getId(), String.format("%4.2f",identity), String.format("%4.2f",gapCov1), String.format("%4.2f",gapCov2));
logger.debug("\n"+pair.toString(100));
if (identity > IDENTITY_THRESHOLD && gapCov1<GAP_COVERAGE_THRESHOLD && gapCov2<GAP_COVERAGE_THRESHOLD) {
if ( !chainIds2entities.containsKey(c1.getId()) &&
!chainIds2entities.containsKey(c2.getId())) {
logger.debug("Creating Compound with chains {},{}",c1.getId(),c2.getId());
EntityInfo ent = new EntityInfo();
ent.addChain(c1);
ent.addChain(c2);
ent.setMolId(molId++);
ent.setType(EntityType.POLYMER);
c1.setEntityInfo(ent);
c2.setEntityInfo(ent);
chainIds2entities.put(c1.getId(), ent);
chainIds2entities.put(c2.getId(), ent);
} else {
EntityInfo ent = chainIds2entities.get(c1.getId());
if (ent==null) {
logger.debug("Adding chain {} to entity {}",c1.getId(),c2.getId());
ent = chainIds2entities.get(c2.getId());
ent.addChain(c1);
c1.setEntityInfo(ent);
chainIds2entities.put(c1.getId(), ent);
} else {
logger.debug("Adding chain {} to entity {}",c2.getId(),c1.getId());
ent.addChain(c2);
c2.setEntityInfo(ent);
chainIds2entities.put(c2.getId(), ent);
}
}
if (!areResNumbersAligned(c1, c2)) {
logger.warn("Including 100% identical chains {},{} in same Compound, although they have misaligned residue numbers",
c1.getId(),c2.getId());
}
}
if (identity>1) {
logger.warn("Identity for chains {},{} above 1. {} identicals out of {} non-gap-aligned residues (identity {})",
c1.getId(),c2.getId(),pair.getNumIdenticals(),nonGaps,identity);
logger.warn("\n"+pair.toString(100));
}
if (chainIds2entities.size()==polyChainIndices.size()) // we've got all chains in entities
break outer;
}
}
// anything not in an Entity will be its own Entity
for (int i:polyChainIndices) {
Chain c = polyModels.get(0).get(i);
if (!chainIds2entities.containsKey(c.getId())) {
logger.debug("Creating a 1-member Compound for chain {}",c.getId());
EntityInfo ent = new EntityInfo();
ent.addChain(c);
ent.setMolId(molId++);
c.setEntityInfo(ent);
chainIds2entities.put(c.getId(),ent);
}
}
// now that we've found the entities for first model, let's do the same for the rest of the models
for (int i=1;i<polyModels.size();i++) {
for (Chain chain : polyModels.get(i)) {
EntityInfo e = chainIds2entities.get(chain.getId());
chain.setEntityInfo(e);
e.addChain(chain);
}
}
return chainIds2entities;
}
private static SequencePair<ProteinSequence, AminoAcidCompound> alignProtein(ProteinSequence s1, ProteinSequence s2) {
SubstitutionMatrix<AminoAcidCompound> matrix = SubstitutionMatrixHelper.getIdentity();
GapPenalty penalty = new SimpleGapPenalty(8, 1);
PairwiseSequenceAligner<ProteinSequence, AminoAcidCompound> nw =
Alignments.getPairwiseAligner(s1, s2, PairwiseSequenceAlignerType.GLOBAL, penalty, matrix);
return nw.getPair();
}
private static SequencePair<DNASequence, NucleotideCompound> alignDNA(DNASequence s1, DNASequence s2) {
SubstitutionMatrix<NucleotideCompound> matrix = SubstitutionMatrixHelper.getNuc4_4();
GapPenalty penalty = new SimpleGapPenalty(8, 1);
PairwiseSequenceAligner<DNASequence, NucleotideCompound> nw =
Alignments.getPairwiseAligner(s1, s2, PairwiseSequenceAlignerType.GLOBAL, penalty, matrix);
return nw.getPair();
}
private static SequencePair<RNASequence, NucleotideCompound> alignRNA(RNASequence s1, RNASequence s2) {
SubstitutionMatrix<NucleotideCompound> matrix = SubstitutionMatrixHelper.getNuc4_4();
GapPenalty penalty = new SimpleGapPenalty(8, 1);
PairwiseSequenceAligner<RNASequence, NucleotideCompound> nw =
Alignments.getPairwiseAligner(s1, s2, PairwiseSequenceAlignerType.GLOBAL, penalty, matrix);
return nw.getPair();
}
private static int getNumGaps(SequencePair<?, ?> pair) {
int numGaps = 0;
for (int alignmentIndex=1;alignmentIndex<=pair.getLength();alignmentIndex++) {
if (pair.hasGap(alignmentIndex)) numGaps++;
}
return numGaps;
}
private static int getNumGapsQuery(SequencePair<?, ?> pair) {
int numGaps = 0;
for (int alignmentIndex=1;alignmentIndex<=pair.getLength();alignmentIndex++) {
if (pair.getCompoundInQueryAt(alignmentIndex).getShortName().equals("-")) {
numGaps++;
}
}
return numGaps;
}
private static int getNumGapsTarget(SequencePair<?, ?> pair) {
int numGaps = 0;
for (int alignmentIndex=1;alignmentIndex<=pair.getLength();alignmentIndex++) {
if (pair.getCompoundInTargetAt(alignmentIndex).getShortName().equals("-")) {
numGaps++;
}
}
return numGaps;
}
private static boolean isProteinSequence(String str) {
try {
new ProteinSequence(str);
} catch (CompoundNotFoundException e) {
return false;
}
return true;
}
private static boolean isDNASequence(String str) {
try {
new DNASequence(str);
} catch (CompoundNotFoundException e) {
return false;
}
return true;
}
private static boolean isRNASequence(String str) {
try {
new RNASequence(str);
} catch (CompoundNotFoundException e) {
return false;
}
return true;
}
/**
* Returns the ProteinSequence or null if one can't be created
* @param str
* @return
*/
private static ProteinSequence getProteinSequence(String str) {
try {
ProteinSequence s = new ProteinSequence(str);
return s;
} catch (CompoundNotFoundException e) {
logger.error("Unexpected error when creating ProteinSequence",e);
}
return null;
}
/**
* Returns the DNASequence or null if one can't be created
* @param str
* @return
*/
private static DNASequence getDNASequence(String str) {
try {
DNASequence s = new DNASequence(str);
return s;
} catch (CompoundNotFoundException e) {
logger.error("Unexpected error when creating DNASequence ",e);
}
return null;
}
/**
* Returns the RNASequence or null if one can't be created
* @param str
* @return
*/
private static RNASequence getRNASequence(String str) {
try {
RNASequence s = new RNASequence(str);
return s;
} catch (CompoundNotFoundException e) {
logger.error("Unexpected error when creating RNASequence ",e);
}
return null;
}
}