private void get_uniprot_mods()
{
var mods = topdown_ptm_set.ptm_combination.Where(p => !Proteoform.modification_is_adduct(p.modification))
.Select(ptm => UnlocalizedModification.LookUpId(ptm.modification)).ToList().Distinct().OrderBy(m => m).ToList();
topdown_uniprot_mods = "";
string add = "";
if (Sweet.lollipop.theoretical_database.theoreticals_by_accession.ContainsKey(Sweet.lollipop.target_proteoform_community.community_number))
{
Sweet.lollipop.theoretical_database.theoreticals_by_accession[Sweet.lollipop.target_proteoform_community.community_number].TryGetValue(accession.Split('_')[0].Split('-')[0], out var matching_theoretical);
if (matching_theoretical != null)
{
foreach (string mod in mods)
{
// positions with mod
List <int> theo_ptms = matching_theoretical.First().ExpandedProteinList.SelectMany(p => p
.OneBasedPossibleLocalizedModifications)
.Where(p => p.Key >= topdown_begin && p.Key <= topdown_end &&
p.Value.Select(m => UnlocalizedModification.LookUpId(m)).Contains(mod))
.Select(m => m.Key).ToList();
if (theo_ptms.Count > 0)
{
add += mod + " @ " + string.Join(", ", theo_ptms) + "; ";
}
if (topdown_ptm_set.ptm_combination.Where(ptm => !Proteoform.modification_is_adduct(ptm.modification)).Select(ptm => UnlocalizedModification.LookUpId(ptm.modification))
.Count(m => m == mod) > theo_ptms.Count)
{
topdown_novel_mods = true;
}
}
topdown_uniprot_mods += add;
if (add.Length == 0)
{
topdown_uniprot_mods += "N/A";
}
foreach (var ambig_id in ambiguous_topdown_hits)
{
Sweet.lollipop.theoretical_database.theoreticals_by_accession[Sweet.lollipop.target_proteoform_community.community_number].TryGetValue(accession.Split('_')[0].Split('-')[0], out var matching_ambig_theoretical);
if (matching_ambig_theoretical != null)
{
var ambig_mods = ambig_id.ptm_list.Where(p => !Proteoform.modification_is_adduct(p.modification))
.Select(ptm => UnlocalizedModification.LookUpId(ptm.modification)).ToList().Distinct().OrderBy(m => m).ToList();
topdown_uniprot_mods += " | ";
add = "";
foreach (var mod in ambig_mods)
{
// positions with mod
List <int> theo_ptms = matching_ambig_theoretical.First().ExpandedProteinList.SelectMany(p => p
.OneBasedPossibleLocalizedModifications)
.Where(p => p.Key >= ambig_id.begin && p.Key <= ambig_id.end &&
p.Value.Select(m => UnlocalizedModification.LookUpId(m)).Contains(mod))
.Select(m => m.Key).ToList();
if (theo_ptms.Count > 0)
{
add += mod + " @ " + string.Join(", ", theo_ptms) + "; ";
}
if (ambig_id.ptm_list.Where(ptm => !Proteoform.modification_is_adduct(ptm.modification)).Select(ptm => UnlocalizedModification.LookUpId(ptm.modification))
.Count(m => m == mod) > theo_ptms.Count)
{
topdown_novel_mods = true;
}
}
}
topdown_uniprot_mods += add;
if (add.Length == 0)
{
topdown_uniprot_mods += "N/A";
}
}
}
}
}
public void identify_experimentals()
{
HashSet <ExperimentalProteoform> identified_experimentals = new HashSet <ExperimentalProteoform>();
if (Sweet.lollipop.identify_from_td_nodes)
{
foreach (TopDownProteoform topdown in experimental_proteoforms.Where(e => e.topdown_id))
{
Sweet.lollipop.theoretical_database
.theoreticals_by_accession[Sweet.lollipop.target_proteoform_community.community_number]
.TryGetValue(topdown.accession.Split('_')[0].Split('-')[0], out var t);
if (t != null && t.Count > 0)
{
TheoreticalProteoform theoretical =
new TheoreticalProteoform(topdown.accession, topdown.name, topdown.sequence,
t.First().ExpandedProteinList, topdown.modified_mass, topdown.lysine_count,
topdown.topdown_ptm_set, true, false, null);
theoretical.topdown_theoretical = true;
theoretical.new_topdown_proteoform = true;
theoretical.begin = topdown.topdown_begin;
theoretical.end = topdown.topdown_end;
foreach (ExperimentalProteoform e in topdown.identify_connected_experimentals(theoretical, topdown.topdown_begin, topdown.topdown_end,
new PtmSet(topdown.topdown_ptm_set.ptm_combination), null))
{
identified_experimentals.Add(e);
}
}
}
}
foreach (TheoreticalProteoform t in theoretical_proteoforms.OrderBy(t => t.topdown_theoretical))
{
lock (identified_experimentals)
foreach (ExperimentalProteoform e in t.identify_connected_experimentals(t, t.begin, t.end, t.ptm_set, t.linked_proteoform_references))
{
identified_experimentals.Add(e);
}
}
//Continue looking for new experimental identifications until no more remain to be identified
List <ExperimentalProteoform> newly_identified_experimentals = new List <ExperimentalProteoform>(identified_experimentals).OrderBy(p => p.relationships.Count(r => r.candidate_ptmset != null) > 0 ? p.relationships.Where(r => r.candidate_ptmset != null).Min(r => Math.Abs(r.DeltaMass - r.candidate_ptmset.mass)) : 1e6).ThenBy(p => p.modified_mass).ToList();
int last_identified_count = identified_experimentals.Count - 1;
while (newly_identified_experimentals.Count > 0) //&& identified_experimentals.Count > last_identified_count)
{
last_identified_count = identified_experimentals.Count;
HashSet <ExperimentalProteoform> tmp_new_experimentals = new HashSet <ExperimentalProteoform>();
foreach (ExperimentalProteoform id_experimental in newly_identified_experimentals)
{
{
lock (identified_experimentals) lock (tmp_new_experimentals)
foreach (ExperimentalProteoform new_e in id_experimental.identify_connected_experimentals(id_experimental.linked_proteoform_references.First() as TheoreticalProteoform, id_experimental.begin,
id_experimental.end, id_experimental.ptm_set, id_experimental.linked_proteoform_references))
{
identified_experimentals.Add(new_e);
tmp_new_experimentals.Add(new_e);
}
}
}
newly_identified_experimentals = new List <ExperimentalProteoform>(tmp_new_experimentals);
}
List <string> topdown_ids = Sweet.lollipop.topdown_proteoforms
.Select(p => p.accession.Split('_')[0].Split('-')[0] + "_" + p.sequence + "_" + string.Join(", ", p.topdown_ptm_set.ptm_combination.Where(m => m.modification.ModificationType != "Deconvolution Error").Select(ptm => UnlocalizedModification.LookUpId(ptm.modification)).OrderBy(m => m))).ToList();
//determine identified experimentals that are adducts
//checks if any experimentals have same mods as e's ptmset, except e has additional adduct only mods.
Parallel.ForEach(experimental_proteoforms, e =>
{
e.adduct =
e.linked_proteoform_references != null &&
e.ptm_set.ptm_combination.Any(m => Proteoform.modification_is_adduct(m.modification)) &&
experimental_proteoforms.Any(l =>
l.linked_proteoform_references != null &&
l.gene_name.get_prefered_name(Lollipop.preferred_gene_label) == e.gene_name.get_prefered_name(Lollipop.preferred_gene_label) &&
l.ptm_set.ptm_combination.Count < e.ptm_set.ptm_combination.Count &&
e.ptm_set.ptm_combination.Where(m => l.ptm_set.ptm_combination.Count(p => UnlocalizedModification.LookUpId(p.modification) == UnlocalizedModification.LookUpId(m.modification)) != e.ptm_set.ptm_combination.Count(p => UnlocalizedModification.LookUpId(p.modification) == UnlocalizedModification.LookUpId(m.modification)))
.Count(p => !Proteoform.modification_is_adduct(p.modification))
== 0
);
if (e as TopDownProteoform != null)
{
(e as TopDownProteoform).set_correct_id();
}
if (e.linked_proteoform_references != null)
{
var mods = e.ptm_set.ptm_combination.Where(p => !Proteoform.modification_is_adduct(p.modification))
.Select(ptm => UnlocalizedModification.LookUpId(ptm.modification)).ToList().Distinct().OrderBy(m => m).ToList();
e.uniprot_mods = "";
string add = "";
foreach (string mod in mods)
{
// positions with mod
List <int> theo_ptms = (e.linked_proteoform_references.First() as TheoreticalProteoform).ExpandedProteinList.SelectMany(p => p
.OneBasedPossibleLocalizedModifications)
.Where(p => p.Key >= e.begin && p.Key <= e.end &&
p.Value.Select(m => UnlocalizedModification.LookUpId(m)).Contains(mod))
.Select(m => m.Key).ToList();
if (theo_ptms.Count > 0)
{
add += mod + " @ " + string.Join(", ", theo_ptms) + "; ";
}
if (e.ptm_set.ptm_combination.Where(ptm => ptm.modification.ModificationType != "Deconvolution Error" && !Proteoform.modification_is_adduct(ptm.modification)).Select(ptm => UnlocalizedModification.LookUpId(ptm.modification))
.Count(m => m == mod) > theo_ptms.Count)
{
e.novel_mods = true;
}
}
e.uniprot_mods += add;
if (add.Length == 0)
{
e.uniprot_mods += "N/A";
}
foreach (var ambig_id in e.ambiguous_identifications)
{
var ambig_mods = ambig_id.ptm_set.ptm_combination.Where(p => !Proteoform.modification_is_adduct(p.modification))
.Select(ptm => UnlocalizedModification.LookUpId(ptm.modification)).ToList().Distinct().OrderBy(m => m).ToList();
e.uniprot_mods += " | ";
add = "";
foreach (var mod in ambig_mods)
{
// positions with mod
List <int> theo_ptms = ambig_id.theoretical_base.ExpandedProteinList.SelectMany(p => p
.OneBasedPossibleLocalizedModifications)
.Where(p => p.Key >= ambig_id.begin && p.Key <= ambig_id.end &&
p.Value.Select(m => UnlocalizedModification.LookUpId(m)).Contains(mod))
.Select(m => m.Key).ToList();
if (theo_ptms.Count > 0)
{
add += mod + " @ " + string.Join(", ", theo_ptms) + "; ";
}
if (ambig_id.ptm_set.ptm_combination.Where(ptm => ptm.modification.ModificationType != "Deconvolution Error" && !Proteoform.modification_is_adduct(ptm.modification)).Select(ptm => UnlocalizedModification.LookUpId(ptm.modification))
.Count(m => m == mod) > theo_ptms.Count)
{
e.novel_mods = true;
}
}
e.uniprot_mods += add;
if (add.Length == 0)
{
e.uniprot_mods += "N/A";
}
}
}
//determine level #
e.proteoform_level_description = "";
if (e.linked_proteoform_references == null)
{
e.proteoform_level = 5;
e.proteoform_level_description = "Unidentified";
}
else if (e.ambiguous_identifications.Count == 0)
{
if (e.ptm_set.ptm_combination.Count == 0)
{
e.proteoform_level = 1;
}
else
{
e.proteoform_level = 2;
e.proteoform_level_description += "PTM localization ambiguity; ";
}
//check if accessions had been grouped in constructing the theoretical database
if ((e.linked_proteoform_references.First() as TheoreticalProteoform).ExpandedProteinList.SelectMany(p => p.AccessionList).Select(a => a.Split('_')[0]).Distinct().Count() > 1)
{
e.proteoform_level += 1;
e.proteoform_level_description += "Gene ambiguity; ";
}
}
else
{
var unique_accessions = new List <string>()
{
e.linked_proteoform_references.First().accession.Split('_')[0].Split('-')[0]
}.Concat(e.ambiguous_identifications.Select(a => a.theoretical_base.accession.Split('_')[0].Split('-')[0])).Distinct();
var unique_sequences = new List <string>()
{
ExperimentalProteoform.get_sequence(e.linked_proteoform_references.First() as TheoreticalProteoform, e.begin, e.end)
}.
Concat(e.ambiguous_identifications.Select(a => ExperimentalProteoform.get_sequence(a.theoretical_base, a.begin, a.end))).Distinct();
var unique_PTMs = new List <string>()
{
string.Join(", ", e.ptm_set.ptm_combination.Where(m => m.modification.ModificationType != "Deconvolution Error").Select(ptm => UnlocalizedModification.LookUpId(ptm.modification)).OrderBy(m => m))
}.Concat(e.ambiguous_identifications.Select(a => string.Join(", ", a.ptm_set.ptm_combination.Where(m => m.modification.ModificationType != "Deconvolution Error").Select(ptm => UnlocalizedModification.LookUpId(ptm.modification))))).Distinct();
int gene_ambiguity = unique_accessions.Count() > 1 ? 1 : 0;
//check if accessions had been grouped in constructing the theoretical database
if ((e.linked_proteoform_references.First() as TheoreticalProteoform).ExpandedProteinList.SelectMany(p => p.AccessionList).Select(a => a.Split('_')[0]).Distinct().Count() > 1)
{
gene_ambiguity = 1;
}
int sequence_ambiguity = unique_sequences.Count() > 1 ? 1 : 0;
int PTM_ambiguity = unique_PTMs.Count() > 1 ? 1 : 0;
int PTM_location = e.ptm_set.ptm_combination.Count(m => m.modification.ModificationType != "Deconvolution Error") > 0 || e.ambiguous_identifications.Any(a => a.ptm_set.ptm_combination.Count(m => m.modification.ModificationType != "Deconvolution Error") > 0) ? 1 : 0;
e.proteoform_level = 1 + gene_ambiguity + sequence_ambiguity + PTM_ambiguity + PTM_location;
if (gene_ambiguity > 0)
{
e.proteoform_level_description += "Gene ambiguity; ";
}
if (sequence_ambiguity > 0)
{
e.proteoform_level_description += "Sequence ambiguity; ";
}
if (PTM_ambiguity > 0)
{
e.proteoform_level_description += "PTM identity ambiguity; ";
}
if (PTM_location > 0)
{
e.proteoform_level_description += "PTM localization ambiguity; ";
}
}
if (e.proteoform_level == 1)
{
e.proteoform_level_description = "Unambiguous";
}
//determine if new intact-mass ID
e.new_intact_mass_id = false;
if (!e.topdown_id && e.linked_proteoform_references != null && e.ambiguous_identifications.Count == 0)
{
string this_id = string.Join(",", (e.linked_proteoform_references.First() as TheoreticalProteoform).ExpandedProteinList.SelectMany(p => p.AccessionList.Select(a => a.Split('_')[0])).Distinct()) + "_" + ExperimentalProteoform.get_sequence(e.linked_proteoform_references.First() as TheoreticalProteoform, e.begin, e.end) + "_" + string.Join(", ", e.ptm_set.ptm_combination.Where(m => m.modification.ModificationType != "Deconvolution Error").Select(ptm => UnlocalizedModification.LookUpId(ptm.modification)).OrderBy(m => m));
if (!topdown_ids.Any(t => this_id.Split('_')[0].Split(',').Contains(t.Split('_')[0]) &&
this_id.Split('_')[1] == t.Split('_')[1] && this_id.Split('_')[2] == t.Split('_')[2]))
{
e.new_intact_mass_id = true;
}
}
});
if (Sweet.lollipop.remove_bad_connections)
{
if (theoretical_proteoforms.Count > 0 || (Sweet.lollipop.identify_from_td_nodes && experimental_proteoforms.Count(e => e.topdown_id) > 0))
{
Parallel.ForEach(relations, r =>
{
r.Accepted = r.Identification;
});
}
}
}