lfetch.py

# MIT License

# Copyright (c) 2021 Luca Gagliardi 
# Affiliation Istituto Italiano di tecnologia


#MOAD database: 
# "Since all structures in
# Binding MOAD must contain a valid ligand, the likelihood of an
# invalid ligand occupying a biologically relevant site is greatly
# reduced. While it is still possible, the rate of such occurrence is
# much less than using all the structures in the Protein Data Bank"


URL = "http://bindingmoad.org/pdbrecords/index/" 

import os
import sys
import glob 
import re 
import shutil
import subprocess
import numpy as np
import requests
from requests.exceptions import HTTPError
from time import time, strftime, localtime
from datetime import timedelta

# import progressbar
from time import sleep
from sys import exit

"""
REQUIREMENTS:
Pip install the required libraries
If --PQR option, must install pdb2pqr: https://github.com/Electrostatics/pdb2pqr


INPUT: Structure in pdb format. For database building mode, the pdbs must be in the working directory. 
For the manual mode (default) if the pdb is not found in the working directory, it will be automatically downloaded

OUTPUT: 
1. ligandMap file containing ligand(s) name for queried structure(s).
2. pdb or xyz file containing ligand heavy atoms (ligand extraction filters out Hidrogens)
Ligand names are fetched from the MOAD database: "http://bindingmoad.org/pdbrecords/index/"  . Only Valid ligands are considered.
The naming scheme is un-ambiguous and inspired from the MOAD database. CAREFUL: if a (ligand) file with the same name exist, 
a number will be appended to the created ligand (pdb or coordinate) file.
OPTIONAL: 
a. Convert to pqr (purged of HETATM and extracted ligands) queried structure(s) using pdb2pqr software https://www.ics.uci.edu/~dock/pdb2pqr/userguide.html using AMBER force field.
b. Automatically process all PDBs in the working directory.
c. If b., given a "chunk size" can separate the outputs (ligandMap, pqrs and ligand files ) in separate directories.
d. Comment out in the ligandMap file ligands which do not perfeclty match with what expected from MOAD. 
Behavior and error handling: 
1. If pdb2pqr cannot reconstruct atom, delete the problematic line and try again.
2. If a ligand is not found in MOAD or not "Valid" according to MOAD criterion is won't be associated to the structure
3. Ligands which have a incomplete matching to what expected from the MOAD database are signalled in the ligandMap file.
The option "--safe" "skips" any partial match (see above). Similarly, those structures which required 1., are labelled in the ligandMap file.

ACKNOLEDGMENTS:
This is a small accessory project which required few coding hours. Still I would appreciate an acknowledgment if this helped you save some time.
Luca Gagliardi, MOAD_ligandFinder, (2021) GitHub repository.

"""

#### USEFUL FUNCTIONS
def file_len(fname):
    with open(fname) as f:
        for i, l in enumerate(f):
            pass
    return i + 1

###### USEFUL CLASSES
# * Time profiling class

class ContinueI(Exception):
    pass

def secondsToStr(elapsed=0):
    if elapsed ==0 :
        return strftime("LOCAL TIME = %Y-%m-%d %H:%M:%S", localtime())
    else:
        return "ELAPSED TIME: "+ str(timedelta(seconds=elapsed))


class Crono(object):
    def init(self):
        self._elapsed=0
        self._start=time()
        return secondsToStr(self._elapsed)
    def get(self):
        end=time()
        self._elapsed=end-self._start
        return secondsToStr(self._elapsed)




#########
# * Error handler class

_warning = "<WARNING> "
_break = "<ERROR> "
class Error(object):
    n_errors = 0
    def __init__(self):
        self.value = 0
        self.info = " "
        self._status = None
    def reset(self):
        self.__init__()
    def partial_reset(self):
        self.info = ""
        self._status =None
    def put_value(self,n):
        #safe writing avoids to overwrite major errors
        if((self.value!=2)and(self.value!=3)):
            self.value=n
        return 

    def build_status(self):
        if((self.value==1)):
            self._status = _warning
        elif((self.value==2)):
            self._status = _break
        elif (self.value==3):
            self._status = _warning
        else:
            pass
        return
    def get_info(self):
        self.build_status()
        # print(self._status + self.info)
        return self._status + self.info
    def write(self,errFile):
        try:
            errFile.write("\n "+self.get_info())
        except OSError:
            raise NotImplementedError("Error log file not found..")
        return
    
    def handle(self,errFile):
        #OBS: Only when errors are handled the static counter is updated
        if(self.value==0): #do nothing
            # self.reset()
            return  
        if self.info=="":
            return
        Error.n_errors +=1
        try:
            errFile.write(self.get_info()+"\n ")
        except OSError:
            raise NotImplementedError("Error log file not found..")
        if(self.value == 4):
            errFile.close()
            try:
                raise Exception("Exiting for major error")
            except Exception:   
                print("Exiting for major error")
                exit()
        self.partial_reset()
        return

#######################################
#####

########## Query function for MOAD #########
#/pdbrecords/exclusion/4/1hel
def queryMOAD(pdb_name,patience):
    """
    Given a pdb name, returns the number of valid ligands with a map than can be used (from extractLigand())
    to extract the ligand coordinates from the pdb file, distinguishing between separate ligands.
    To do so the functions fetch data from the MOAD database.
    """
    err = Error()
    i=0
    while(1):
        try:
            response = requests.get(URL+pdb_name,allow_redirects=True)
            # print(response.url)
            response.raise_for_status()
            break
        except HTTPError:
            if(i>3 or (not patience)):#try 3 times this
                print("HTTP error occurred: No match in the MOAD database for "+pdb_name)
                err.value = 2
                err.info = "HTTP error occurred. No match in the MOAD database for "+pdb_name
                return err,[]
            print("\r\t\tHTTP error: Attempt  " +str(i), end='')
        except Exception:
            if(i>=300 or (not patience)):# 5 mins of attempts
                print('Other error occurred for '+pdb_name+' (probably internet connection issues..)')  
                err.value = 2
                err.info = "Other error occurred for "+pdb_name+" (probably internet connection issues..)"
                return err,[]
            print("\r\t\tConnection error: Attempt  " +str(i), end='')
        sleep(1)
        i+=1

        

    #OBS also from response url I could deduce no match..
    raw = response.text
    pageTxt = [x.strip() for x in raw.split('\n')]
    
    #Verify entry exists in MOAD 
    moadError = "\t"
    gotMatch = False
    ligNames = set() #set is like a dict with only keys (duplicates are not considered)
    for c,line in enumerate(pageTxt):
        match=re.match("(<p class=\"sidebar-title\">Showing PDB:\s*)([^</p>]*)",line)
        match2 = re.match("([^.]+\s*<br/>)",line)
        matchLig =re.match("(^Ligand no:\s*\d+)([;?\s]*Ligand:\s*)([^;]*)",line)
        if match2:
            # moadError= "\t" + match2.group() + "\t" + pageTxt[c+1]
            moadError= "The pdb " + pdb_name + " was excluded from MOAD for the following reason:  " + pageTxt[c+1]
        if match:
            gotMatch=True
        if matchLig:
            # print(matchLig.group(2))
            ligNames.add((matchLig.group(3)))
            # got_name = match.group(2)
            # print(got_name)
            # if(got_name == pdb_name):
            #     print(match.group())
            #     print("OK")
            #     break
    if(not gotMatch): 
        err.put_value(2)
        err.info=  moadError
        # print(response.history)
        # print("Ligand or entry excluded from MOAD. Check error log")
        return err,[]

    #Here on I'm sure the page has been correctly loaded
    #Looking for ligands

    # print(len(ligNames),ligNames)

    if not ligNames:
        err.put_value(2)
        err.info="Unkonown error. Unable to find ligands in MOAD for "+pdb_name
        return err,[]
    firstMatch=np.ones(len(ligNames),bool)*False
    
    ligands= []
    s=0
    for l in ligNames:
        #print(l)
        for c,line in enumerate(pageTxt):
            matchname = re.match("<td>"+l+"\s*</td>",line)
            if(matchname and (not firstMatch[s])):
                firstMatch[s] = True
                # print(line)
                nextline = pageTxt[c+1]
                # matchChainRest = re.findall("([A-Z]:[\d]+)",nextline)
                #very rarely chain is a number!
                matchChainRest = re.findall("([\w0-9]:[\d]+)",nextline)
               
                # print(nextline)
                # print(matchChainRest)
                
                # print("Number of distint ligands for current name:",len(matchChainRest))
                namelist = l.split()
                for cr in matchChainRest:
                    #this will be used as filename containing ligand coordinates
                    #set() to remove duplicates
                   
                    name = repr(namelist).replace("[","").replace("]","").replace("'","")
                
                    filename=name.replace(", ", "_")+'_'+cr.replace(":","") 
                    
                    chain,number = re.match("([\w0-9]):([\d]+)",cr).groups()

                    resid = [str(i) for i in range(int(number),int(number)+len(namelist))]
            
                    ligands.append({'filename':filename,'name(s)':namelist ,'chain': chain,'resid(s)':resid})
            
        s+=1   
    
#<fieldset id="fieldset_ligandinfo" class="coolfieldset"> 
                    # <tbody>
                    #                             <tr>
                    #         <td>NAG NAG NAG </td>
                    #         <td>B:1;<br> </td>
                    #         <td>Valid;<br> </td>
                            
    n_ligands = len(ligands)
    if n_ligands==0:
        err.put_value(2)
        err.info="Unkonown error. Unable to find ligands in MOAD for "+pdb_name
        return err,[]
    # print("TOTAL NUMBER VALID DISTINT LIGANDS OF THE QUERY= %d" %n_ligands)
    return err,ligands



def extractLigand(pdbName,dictList,savepath,onlyXYZ,extractPQR,purgePDB):
    '''
    Given the map produced by queryMOAD() and the pdb file, creates xyz files of the heavy atoms of the ligand (*)
    Also produces a temp file containing the pdb without the ligand coordinates EXTRACTED neither HETATM.
    Since there could be some difficulties in extracting ligand coordinates due to mismatch with the MOAD database,
    there are no guarantees the structure is completely purged of ligands before conversion to PQR if ligands expected naming scheme not obserrved.
    However this scenario is rare and a error could prevent the conversion.
    In any case all labelled HETATM are correclty elided before conversion to PQR.

    Any manipulation of the standard file or re-interpretation of the MOAD search pattern is signaled. (examples: 4mdr (only for 1 of the 2 ligands),4mdr )

    *) Heavy atoms are kept recognizing Hydrogens in the ligand (example pdb_code: 1cka)

    NOTE: in purged PDB extraction, if PQR conversion is performed, the line containing SEQADV is also removed
    since this very rarely was creating problems in conversion.
    '''


    import copy 
    
    key_dictionary =[]
    for li in dictList:
        # print(li)
        d2 = copy.deepcopy(li)
        key_dictionary.append(d2)

    import re
    err = Error()
    matchPerLigand = np.zeros(len(key_dictionary)) #0: not match, 1: full match (how expected from MOAD), -1: partial match

    comment =['#', 'REMARK','MASTER', 'END']
    info = ['SOURCE','COMPND','TITLE','HEADER','JRNL','AUTHOR','REVDAT','KEYWDS','EXPDTA']
    crist = ['CRYST1','ORIGX[0-9]','SCALE[0-9]','MTRIX[0-9]','TVECT']
    if(extractPQR):
        primStruct = ['DBREF','SEQRES','MODRES','SITE']#'SEQADV' skipping, sometimes creates problem to keep this line in pd2prq..
    else:
        primStruct = ['DBREF','SEQRES','MODRES','SITE','SEQADV']
    connectivity = ['CONECT','SSBOND','LINK','HYDBND','SLTBRG','CISPEP']
    secStruct = ['HELIX','SHEET','TURN']
    protein = ['ATOM','MODEL','SIGATM','ANISOU','SIGUIJ','TER','ENDMDL']
    het = ['HET\s+','HETNAM','HETSYN','FORMUL'] #HET infos (no coordinates)

    # proteinExtract = ['CRYST1','ATOM','END']

    keep = comment+info+crist+primStruct+secStruct+connectivity+protein+het
    # skip = proteinExtract
    keep = '(?:^% s)' % '|^'.join(keep) #match beginning
 
     
    try:
        pdb_file = open(pdbName+'.pdb','r')
    except Exception :
        err.info = "Did not find pdb file for "+pdbName
        err.put_value(2)
        return err,matchPerLigand

    if(os.stat(pdbName+'.pdb').st_size == 0):
        err.info = "Empty file for  "+pdbName
        err.put_value(2)
        return err,matchPerLigand

        
    pdb_data = pdb_file.readlines()
    
    savepath = savepath +'/'
    
    
    ntrial=[]
    initialLength = []
    for s in range(len(key_dictionary)):
        initialLength.append(len(key_dictionary[s]['name(s)']))
        ntrial.append(0)


    ################### MAIN LOOP FETCHING LIGAND COORDS AND PREPARING TMP FILE FOR PDB2PQR #####################
    ligandFile=[]
    
    if(onlyXYZ):
        extension = ".xyz"
    else:
        extension =".pdb"
    for s,i in enumerate(key_dictionary):
        duplicates = ""
        d=0
        while(1):
            lfname = savepath+i['filename']+duplicates+extension
            if (os.path.isfile(lfname)):
                duplicates = '_'+str(d+1)
                #Modify map externally
                dictList[s]['filename'] = i['filename']+duplicates
            else:
                break
            d+=1
        ligandFile.append(lfname)


    while(1):

        fo=[open(lf,'w') for lf in ligandFile]
        matches = []
        #This tries to not search in order for some resname, since it can happen MOAD entries are more than those actually in the PDB
        #Also we relax on having a partial match. This because sometimes some of the last resnames and ids are missing.
        for s in range(len(key_dictionary)):
            if(ntrial[s]>0):
                del key_dictionary[s]['name(s)'][0] 

        # print(key_dictionary)


        # ******** Build a dictionary of the matching pattern searched ********
        for d in key_dictionary:
            names =d['name(s)'] #sublist of identifiers belonging to same ligand
            chain = d['chain'] #single letter per ligand
            ids = d['resid(s)']  #sublist as long as names
            m = []
            for i in range(len(names)):
                name = names[i]
                resid = ids[i]
                #(?:) non capturing group
                m.append("(?:ATOM|HETATM)\s*[\d]+\s+[\S]+\s*[A-Z]*\s*"+name+"\s+"+chain+"\s*"+resid+"[A-Z]*\s+(\-?\d*\.?\d+)\s*(\-?\d*\.?\d+)\s*(\-?\d*\.?\d+)\s+.*([A-Z])\s*$")
        #NOT matching H at the end: #m.append("(?:ATOM|HETATM)\s+[\d]+\s+[\S]+\s*[A-Z]*\s*"+name+"\s+"+chain+"\s*"+resid+"\s+(\-*\d*\.?\d+)\s+(\-*\d*\.?\d+)\s+(\-*\d*\.?\d+)(?!.*\\bH\\b).*$")
                #m.append("HETATM\s+[\d]+\s+[\S]+\s*[A-Z]*\s*"+name+"\s+"+chain+"\s*"+resid+"\s+(\-*\d*\.?\d+)\s+(\-*\d*\.?\d+)\s+(\-*\d*\.?\d+)(?!.*\\bH\\b).*$")
                #                            ^letter, number and some special characters                                         ^Do not take H atoms
            matches.append(m)
        ##########
        #######
        make_purgedPDB=False
        if(extractPQR or purgePDB):
            make_purgedPDB=True 
            if(purgePDB):
                tmpFile = open(pdbName+'_clean.pdb','w') # contains original files without FOUND ligand and hetatm
            else:
                tmpFile=open('tmp','w')
        # print(matches)
        ligandAtoms = 0
        # print(matches)
        matchPerResName =[np.zeros(len(l)) for l in matches] #mlist is whithin a single ligand

        for line in pdb_data:
            ligandMatched=False
            HEAVY =True
            for s,mlist in enumerate(matches):
                if not HEAVY:
                    break
                for k,m in enumerate(mlist):
                    match = re.match(m,line)
                    if match:
                        matchPerResName[s][k] = 1
                        # print (match.groups())
                        if ((match.groups()[-1] == 'H')or (match.groups()[-1] == 'D')):
                            HEAVY = False
                            break
                        ligandAtoms+=1
                        # print(line)
                        # print(match.groups())
                        coordline = tuple([it for it in map(lambda x: float(x), match.groups()[0:3])])
                        # print(coordline)
                        if(onlyXYZ):
                            fo[s].write("%f\t%f\t%f\n"%coordline)
                        else:
                            fo[s].write(line)
                        ligandMatched = True
                        break 
            if not HEAVY: 
                #Here only if ligand line is matched
                #skipping also the line for the tmp file-->Avoid spurious light ligand atom in purged pdb..
                continue
            if (not ligandMatched and make_purgedPDB):
                #write wathever is not ligand nor HETATM nor not heavy
                if(re.match(keep,line)):
                    # print(line)
                    tmpFile.write(line) #write all lines starting with "keep" to tmp file
                    continue
        if(make_purgedPDB):
            tmpFile.close()
        for f in fo:
            f.close() 
        #######
        #Here on matchPerResName contains a map of all RES names matched per ligand. Where the first index runs over the ligands
        # print("matchArray:",matchPerResName)
        # print("trials array:",ntrial)
        ok=0
        fail =0
        for s,l in enumerate(matchPerResName):
            # print(l)
            # print(str(initialLength[s]) +" VS " +str(np.sum(l)))
            #s=ligand index
            #Tollerance over partial matches + trying to correct for bad alignement in the MOAD database
            #We use initial lenght because if a match isot satisfied with less than half, is not accepted since the discrepancy with MOAD is too big
            if((len(key_dictionary[s]['name(s)'])==0) or (len(l)<initialLength[s]//2)):
                fail +=1
                ntrial[s] = -1
            elif ((np.sum(l)<initialLength[s]//2 )and(len(key_dictionary[s]['name(s)'])>1)):
                ntrial[s]+=1
            else:
                if(np.sum(l) == initialLength[s]):
                    matchPerLigand[s]=1
                else:
                    #partial match
                    err.put_value(1)
                    matchPerLigand[s]=-1
                    # ligandInfo = repr(key_dictionary[s]["name(s)"]).replace("[","").replace("]","").replace("'","").replace(", ","_")+" chain="+key_dictionary[s]["chain"]
                    ligandInfo = key_dictionary[s]['filename']
                    err.info += "\n Corrected "+ligandInfo+ "  of PDB= "+pdbName+ ": Needed to skip first "+str(ntrial[s]+1)+" residue names out of "+str(initialLength[s])
                ok+=1
        # print("**OKS:", ok)
        # print("**FAILS:", fail)
        ### END CONDITION ##
        if (ok+fail ==len(matchPerResName)):
            if(ok==0):
                err.info="**Did not suceed fetching ligands for "+pdbName
                err.put_value(2)
                for s in range(len(key_dictionary)):
                    subprocess.run(['rm',ligandFile[s]])
            elif(fail>0):
                err.info +="** Failed to fetch one of the ligands"
                for s in range(len(key_dictionary)):
                    if(matchPerLigand[s]==0):
                        subprocess.run(['rm',ligandFile[s]])
            break

    return err,matchPerLigand

####################################
#####################


def removeLine(linesToskip,inName):
    '''
    Remove problematic line from pdb for pqr conversion.
    This info is gathered from the error message of pdb2pqr.

    TODO: In the case where the purged pdb file is not removed, since its output is user required,
    the final file while have those lines removed. This is not very clean and not transparent for user.
    In case a tmp file is produced for the only purpose of pqr creation, this is perfectly OK,
    the file is removed from the script at the end.
    '''
    continueI = ContinueI()
    matchingLines = []
    info = []
    for line in linesToskip:
        # print(line)
        m = re.search("\s*Heavy atoms missing from ([A-Z]+)\s+([A-Z])\s+([\d]+)\\:",line)
        if m:
            # print("***"+line)
            resname = m.groups()[0]
            chain = m.groups()[1]
            resid = m.groups()[2]
            info.append({'resname':resname,'chain':chain,'resid':resid})
            matchingLines.append("ATOM\s*[\d]+\s*[\S]+\s+"+resname+"\s+"+chain+"\s*"+resid+"\s+(\-?\d*\.?\d+)\s*(\-?\d*\.?\d+)\s*(\-?\d*\.?\d+)")
    oldFile = open(inName,'r')
    oldData = oldFile.readlines()
    oldFile.close()
    newFile = open(inName,'w')
    for line in oldData:
        try:
            for ml in matchingLines:
                if re.match(ml,line):
                    raise continueI
        except ContinueI:
            continue#skip the line
        newFile.write(line)
    
    newFile.close()
    return len(matchingLines),info
    





def chunks(lst, n):
    """Yield successive n-sized chunks from lst."""
    if n==0:
        yield lst
        return
    for i in range(0, len(lst), n):
        yield lst[i:i + n]



def buildPQR(n,isEX,inName,savepath = '.',move=False,skipLarge = False):
    err = Error()
    comment = ""
    outname = n+'.pqr'
    savepath = savepath +'/'
    if(isEX):
            pdb2pqrCall = 'pdb2pqr --drop-water --ff=amber --chain '+inName+' '+outname
    else:
        pdb2pqrCall = "pdb2pqr30 --drop-water --keep-chain --ff=AMBER "+inName+' ' +outname
    # print(pdb2pqrCall)
    tryingToFix = True
    if(isEX):
        while tryingToFix:
            try:
                out=subprocess.check_output(pdb2pqrCall,shell=True,stderr=subprocess.STDOUT)
                tryingToFix = False
            except subprocess.CalledProcessError as grepexc:                                                                                                   
            # print ("error code", grepexc.returncode, grepexc.output)
                errlines=str(grepexc.output).split('\\n')
                # print(errlines)
                nHeavyAtomMissing,rmvdAtoms = removeLine(errlines,inName)
            # print(nHeavyAtomMissing)
                if(nHeavyAtomMissing>0):
                    tryingToFix = True
                    # try:
                    err.put_value(1)
                    err.info+="** Removed problematic heavy atom from "+n+": "+str(rmvdAtoms)+"** "
                    comment = "\t# --> a warning was produced in pdb2pqr conversion."
                    # out=subprocess.check_output(pdb2pqrCall,shell=True,stderr=subprocess.STDOUT)
                    
                    # except subprocess.CalledProcessError as grepexc:
                else:
                    err.put_value(2)
                    err.info+= "\nCannot correct file  "+n+"  Unexpected exception.\n" +str(grepexc.output)+ "\nSkipping "   
                    return err,comment
            except Exception:
                print("IMPORTANT WARNING: Unexpected exception. Skipping")
                err.put_value(2)
                err.info = "Unexpected exception on  "+n+ "\n ORIGINAL ERROR MESSAGE FROM pdb2pqr:\n"+str(grepexc.output)+"\n-----------"
                return err,comment
    else:
        #Eror handling different for pdb2pqr30 and must be grasped from output
        while tryingToFix:
            try:
                out=subprocess.check_output(pdb2pqrCall,shell=True,stderr=subprocess.STDOUT) 
                out = str(out)
                tryingToFix = False
                # print(out)
                if(re.search("(CRITICAL)",out)):
                    checkout=out.split('\\n')
                    nHeavyAtomMissing,rmvdAtoms = removeLine(checkout,inName)
                    # print(nHeavyAtomMissing)
                    # print(rmvdAtoms)
                    if(nHeavyAtomMissing>0):
                        # try:
                        err.put_value(1)
                        err.info+="** Removed problematic heavy atom from "+n+": "+str(rmvdAtoms)+"** "
                        comment = "\t  # --> a warning was produced in pdb2pqr conversion."
                        tryingToFix = True
                            # out=subprocess.check_output(pdb2pqrCall,shell=True,stderr=subprocess.STDOUT)
                        # except subprocess.CalledProcessError as grepexc:
                        # err.put_value(2)
                        # err.info += "Unhandled exception on "+n+ "\n ORIGINAL ERROR MESSAGE FROM pdb2pqr:\n"+str(grepexc.output)+"\n-----------"
                    else:
                        err.put_value(2)
                        err.info+= "\nCannot correct file"+n+"Unexpected exception.\n Skipping "   
                        return err,comment
            except Exception:
                print("IMPORTANT WARNING: Unexpected exception. Skipping")
                err.put_value(2)
                err.info = "Unexpected exception on "+n+ "\n ORIGINAL ERROR MESSAGE FROM pdb2pqr:\n"+str(subprocess.CalledProcessError)+"\n-----------"
                return err,comment
    if(skipLarge):
        lenght = file_len(outname)
        if(lenght>10000):
            err.put_value(3)
            err.info = "Skipping " +n+ " since very large (%d lines). To disable this behavior, turn off the option."%lenght
            subprocess.run(['rm',outname])
            return err,comment
    if(move):
        subprocess.run(['mv',outname,savepath])

    return err,comment

########################
############################# MAIN ################

#ERROR HANDLING:
#2-3 print warning and causes skipping
#1 only prints warning


#check that pdbtopqr is installed
def main(argv):
    import getopt

    
    onlyXYZ = False
    excludeLage = False
    isDatabase =False
    isChunk = False
    purgePDB = False
    extractPQR = False
    noTollerance =False
    verbose = True
    extension = '.pdb'
    ##OMIT?
    # skip=0

    ###
    try:
        opts, args = getopt.getopt(argv,"dch",["XYZ","excludeLarge","PQR","purgePDB","safe","quiet","help"])
    except getopt.GetoptError:
        print ('uncorrect formatting of options')
        sys.exit(2)
    for opt, arg in opts:
        if opt in["-h","--help"]:
            print("Usage:\npython3 lfetch\nOptions:")
            print("--XYZ: ligands extracted as coordinate files")
            print("--PQR: pdb structures queried are converted to PQR. CAREFUL: needspdb2pqr intalled")
            print("--purgePDB: a copy of the original pdb structure without the extracted ligand is produced")
            print("--safe: Partial matches to MOAD naming scheme are excluded")
            print("--quiet: No info is printed on stdout while running")
            print("-d: \'Database mode\'--> all pdbs in the working folder are analysed")
            print("-c: User can split the result (e.g. extracted ligands) in separate folders defining the size of each chunk")
            input('\n')
            sys.exit()
        if opt in ["--excludeLarge"]:
            excludeLage = True 
        if opt in ["-d"]:
            print("Database operating mode selected")
            isDatabase = True
        if opt in ["-c"]:
            if(isDatabase):
                print("Chunk mode selected")
                isChunk = True
            else:
                print("inconsistency in the optional arguments given : Chunk mode must be associated to database building option -d")
                sys.exit(2)
        if opt in ["--XYZ"]:
            onlyXYZ = True
            extension = '.xyz'
        if opt in ["--PQR"]:
            extractPQR = True
        if opt in ["--purgePDB"]:
            purgePDB = True
        if opt in ["--safe"]:
            noTollerance = True
        if opt in ["--quiet"]:
            verbose = False

    # uIN = input("Insert y for automatic mode. [y/n]")

    success_counter = 0
    err = Error()
    stopWatch = Crono()

    errFile = open("error_log.txt",'w')

    # Check if pdb2pqr installed and set correct path for calling
    #Tollerates both executable and python versions
    if(extractPQR):
        locate=shutil.which('pdb2pqr')
        # print(locate)
        isEX = False
        if(locate==None):
            #Try to find it as the pip3 version
            locate=shutil.which('pdb2pqr30')
            if(locate==None):
                try:
                    raise OSError("pdb2pqr not found.\n")
                except Exception as e:
                    exit(str(e)+'EXIT')
        else:
            isEX=True


    
    buildDatabase = False
    
    ligMapFiles =[]
    if(isDatabase):
        # DATABASE BUILDING MODE 
        buildDatabase =True

        #exclude files containing _ which are ligands or purged pdb
        infileList=[n for n in glob.glob('*.pdb') if "_" not in n]
    
        if not infileList:
            try:
                raise FileNotFoundError("pdb files must be placed in the running folder\n")
            except Exception as e:
                print(str(e)+'EXIT')
                err.value=3
                err.info = str(e)+'EXIT'
        err.handle(errFile)
        if(isChunk):
            nc = int(input("Insert chunk size out of "+str(len(infileList))+'\n'))
        else:
            nc = 0
        #split pdb list into chunks
        nameList = [re.match("(.*)\.pdb",l).groups()[0] for l in infileList]
        c_infile =[]
        for fc in chunks(nameList,nc):
            c_infile.append(fc)
        nc = len(c_infile)
        if(not nameList):
            print("No structures to process in the working directory")
            sys.exit()

        print("Number of structures to process= ",len(nameList))
        print("number of chuncks= ",nc)
        answ = input("proceed? (y/n)\n")
        if (answ=='y'):
            ContinueI
        else:
            sys.exit()
    else:
        ligMapFiles.append(open("ligandMap.txt",'w'))
        ligMapFiles[0].write("# ************** PDB ligand Map *************** \n")
        ligMapFiles[0].write("#\tCreated using '*BuildMap module*\n# Ligand validation based on binding MOAD database.\n")
        ligMapFiles[0].write("# Author L. Gagliardi, Istituto Italiano di Tecnologia\n")
        ligMapFiles[0].write("# "+stopWatch.init())
        ligMapFiles[0].write('\n# --------------\n')
        pass


#############  ******* CORE FUNCTIONS ******* #############################
    done = set()
    patience=False
    loopinf=True
    data = [None]
    local_path =[None]
    here = os.path.abspath(".")
    moveFile =False 
    logfile=open("logfile.txt",'w')
    logfile.write("# List of succesfully processed structures")
    while (loopinf):
        if not buildDatabase:
            local_path[0] = here
            try:
                pdb_name = str(input("Insert pdb name \n"))
                data[0]=[pdb_name]
            except KeyboardInterrupt:
                break
            except :
                exit("a not handled exception occurred..")
        else:
            patience=True
            loopinf =False
            moveFile = True
            data = [l for l in c_infile]
            # print(data,len(data))
            
            if(nc>1):
                local_path =[]
                for i in range(nc):
                    local_folder = str(i+1)
                    isFolder = os.path.isdir(here+'/'+local_folder)
                    if not isFolder:
                        subprocess.run(['mkdir',local_folder])
                    local_path.append(here+'/'+local_folder)
                    ligMapFiles.append(open(local_path[-1]+"/ligandMap.txt",'w'))
                    ligMapFiles[-1].write("# ************** PDB ligand Map *************** \n")
                    ligMapFiles[0].write("#\tCreated using '*lfetch-MOAD_ligandFinder*\n# Ligand validation is based on binding MOAD database.\n")
                    ligMapFiles[0].write("#\thttps://github.com/lucagl/MOAD_ligandFinder.git\n")
                    ligMapFiles[-1].write("# Author L. Gagliardi, Istituto Italiano di Tecnologia\n")
                    ligMapFiles[-1].write("# "+stopWatch.init())
                    ligMapFiles[-1].write('\n# --------------\n')
            else:
                local_path[0] = here+'/output'
                isFolder = os.path.isdir(here+'/output')
                if not isFolder:
                    subprocess.run(['mkdir','output'])
                ligMapFiles.append(open("ligandMap.txt",'w'))
                ligMapFiles[0].write("# ************** PDB ligand Map *************** \n")
                ligMapFiles[0].write("#\tCreated using '*BuildMap module*\n# Ligand validation based on binding MOAD database.\n")
                ligMapFiles[0].write("# Author L. Gagliardi, Istituto Italiano di Tecnologia\n")
                ligMapFiles[0].write("# "+stopWatch.init())
                ligMapFiles[0].write('\n# --------------\n')

            
            total = len(infileList)
            # bar = progressbar.ProgressBar(maxval=total,widgets=[progressbar.Bar('=', '[', ']'), ' ', progressbar.Percentage()])
            # bar.start()
        global_counter = 0
        
        for s,names in enumerate(data):
            logfile.write("\n\n Chunk "+str(s) +": \n")
            for n in names:
                comment1=""
                comment2=""
                if n.lower() in done:
                    continue
                global_counter+=1
                
                # print('\n**'+n)
                err,ligandList = queryMOAD(n,patience)
                # print(ligandList)
                err.handle(errFile)
                if(err.value==2):
                    print("Problem: could not find ligands of " + n + " in MOAD..")
                    # ligMapFiles[s].write('\n# '+str(len(ligandList)) +"\t" + n + "\t Did not found valid ligands. IGNORING")
                    continue
                
                    # print(ligandList)
                stop = 0
                while(stop<=1):
                    err,matched = extractLigand(n,ligandList,savepath=local_path[s],onlyXYZ=onlyXYZ,extractPQR=extractPQR,purgePDB=purgePDB)
                    err.handle(errFile)
                    if err.value == 2:
                        if stop==0:
                            stop+=1
                            print("<ERROR>: Could not extract ligands for "+n+", trying to re-download structure..")
                            err.info="Trying to re-download structure.."
                            err.value=1
                            err.handle(errFile)
                            url = "https://files.rcsb.org/download/"+n+".pdb"
                            print(url)
                            # print(str(["wget", url,'-O',n+".pdb"]))
                            # proc = subprocess.Popen(["wget", url,'-O',n+".pdb"],stdout=subprocess.PIPE, stderr=subprocess.PIPE)
                            # proc.wait()
                            # (stdout, stderr) = proc.communicate()
                            try: 
                                r = requests.get(url, allow_redirects=True)
                                open(n+".pdb",'wb').write(r.content)
                            except HTTPError:
                            # if proc.returncode != 0:
                                # print(stderr)
                                print("Could not download "+n)
                                err.value =2
                                err.handle(errFile)
                                err.info = "Could not (re)download "+n
                                err.handle(errFile)
                                ligMapFiles[s].write('\n# '+str(len(ligandList)) +"\t" + n + "\t <-- Unable to extract ligands. Check error log. IGNORING")
                                break
                        else:
                            print("SKIPPING "+n+". Check error log \n")
                            ligMapFiles[s].write('\n# '+str(len(ligandList)) +"\t" + n + "\t <-- Unable to extract ligands. Check error log. IGNORING")
                            break
                    elif err.value ==1:
                        if(not isDatabase):
                            if(noTollerance):
                                print("<ERROR> Some uncoherency between MOAD and pdb ligand name on "+n+", check errors log..\n")
                            else:
                                print("<WARNING> Some uncoherency between MOAD and pdb ligand name on "+n+", check errors log..\n")
                        # comment1 = "\t\t # --> a warning was produced in ligand extractuon, this structure is less trustable..."
                        break
                    else:
                        break
                if err.value ==2:
                    continue
                if (extractPQR):
                    #build pqr
                    if(purgePDB):
                        inName = n+'_clean.pdb'
                    else:
                        inName = 'tmp'
                    err,comment2 = buildPQR(n,isEX,inName,savepath = local_path[s],move=moveFile,skipLarge=excludeLage)
                    err.handle(errFile)
                else:
                    err.put_value(0)
                comment = comment1+comment2
                # Updating ligMap
                if(err.value==3):
                    if(verbose and (not isDatabase)):
                        print("SKIPPING "+n+" since too large \n")
                    ligMapFiles[s].write('\n# '+str(len(ligandList)) +"\t" + n + "\t <-- Too large! IGNORING")
                    for l in ligandList:
                        lfile=local_path[s]+'/'+l['filename']+extension
                        if(os.path.isfile(lfile)):
                            subprocess.run(['rm',lfile])
                        else:
                            pass
                        
                    continue
                elif err.value==2:
                    print("Problem: SKIPPING "+n+". Check error log \n")
                    ligMapFiles[s].write('\n# '+str(len(ligandList)) +"\t" + n + "\t Unable to extract pqr. Check error log. IGNORING")
                    continue
                else:
                    ligMapFiles[s].write('\n'+str(len(ligandList) - np.sum(np.logical_not(matched))) +"\t" + n +comment) 
                    logfile.write("\n"+n)
                    for k,d in enumerate(ligandList):
                        if(matched[k]==1):
                            ligMapFiles[s].write("\n" + d['filename'])
                        elif(matched[k]==-1):
                            if(noTollerance):
                                lfile=local_path[s]+'/'+d['filename']+extension
                                subprocess.run(['rm',lfile])
                                ligMapFiles[s].write("\n#" + d['filename']+"\t# <-- Partial match with respect to what expected. SAFE MODE=skipping")
                            else:
                                ligMapFiles[s].write("\n" + d['filename']+"\t# <-- Partial match with respect to what expected..")
                        else:
                            ligMapFiles[s].write("\n#" + d['filename']+" <-- NOT found in pdb") 
                            

                
                errFile.flush()
                ligMapFiles[s].flush()
                done.add(n.lower())
                if verbose:
                    if(isDatabase):
                        # print("processed: " +n)
                        print("\r%d / %d of structures processed" % (global_counter,total),end='')
                    else:
                        print("Valid ligands found: ",len(ligandList))
                        if(noTollerance):
                            print("Excluded:",np.sum(matched==0) + np.sum(matched==-1))
                            print("Ligands:", [l['filename'] for l,m in zip(ligandList,matched) if (m != -1) and (m !=0)])
                        else:
                            print("Excluded:",np.sum(matched==0))
                            print("Ligands:", [l['filename'] for l,m in zip(ligandList,matched) if m != 0])
                #     bar.update(global_counter)
                success_counter+=1
    # if buildDatabase:
    #     bar.finish()
        
    errFile.close()

    if(extractPQR and data):
        if(not purgePDB):
            subprocess.run(['rm', 'tmp'])
    
    if(extractPQR):
        if(not isEX):
            #remove <pdbName>.log files generated by pdb2pqr30
            subprocess.run("rm *.log", shell=True)
    for lgmf in ligMapFiles:
        lgmf.close()

    print("TOTAL NUMBER OF STRUCTURES SUCCESFULLY PROCESSED = "+str(success_counter))
    logfile.write("\n\n** TOTAL NUMBER OF STRUCTURES SUCCESFULLY PROCESSED = "+str(success_counter))
    logfile.close()
    
if __name__ == '__main__':
    try:
        main(sys.argv[1:])
    except KeyboardInterrupt:
        print("\nUser exit")
        sys.exit()