# Example: 5-HT2A/2B/2C serotonin receptors, agonist vs antagonist, with vs
# without the Gq heterotrimer
#
# Three closely related Gq/11-coupled serotonin receptors (5-HT2A UniProt
# P28223, 5-HT2B UniProt P41595, 5-HT2C UniProt P28335), each crossed with
# a real agonist and a real antagonist, each ligand predicted BOTH with
# and without the Gq heterotrimer (GNAQ + GNB1 + GNG2) co-folded --
# following the same lesson learned from adrb2_gs_panel: co-folding a G
# protein biases Boltz toward an active-like fold regardless of ligand
# identity, so a fair agonist-vs-antagonist comparison needs the receptor
# alone as well as the physiologically-correct (agonist+Gq) condition.
# Every receptor gets two Protein: blocks sharing one sequence -- one
# with Partners: (the Gq trimer), one without -- exactly as
# adrb2_gs_panel does, extended to a 3x2x2 = 12-target panel: 3
# receptors x 2 ligands x (with/without Gq).
#
# Apo reference structures: genuinely ligand-free, not an antagonist-
# bound "inactive-like" stand-in. Checked entity-by-entity across all 59
# deposited structures for these 3 receptors (not trusting RCSB's summary
# fields, which turned out to have real gaps) -- every single one has a
# real ligand bound, including ones that first looked apo (e.g. what
# looked like a ligand-free 5-HT2B entry turned out to have ergotamine).
# No genuinely apo experimental structure exists for any of the three.
# Instead, each receptor's own apo reference is a Boltz prediction of the
# receptor ALONE (no ligand, no partner) -- a real BoltzMaker target via
# `Ligands: none` (see the 3 apo Protein: blocks below), staged and run
# in the exact same `boltz predict` batch as the 12 ligand-bound targets
# below (one manifest, one campaign, no separate invocation), producing
# reference/*_apo_predicted.cif via boltz_cif/. Clearly a computational
# model, not an experimental one, but unambiguously ligand-free.
#
# All 6 ligands are real, clinically/pharmacologically characterized
# compounds: Risperidone and Psilocin (5-HT2A antagonist/agonist),
# Balovaptan and LSD (5-HT2B antagonist/agonist), SB-242084 and
# Lorcaserin (5-HT2C antagonist/agonist).

Settings:
Output folder: ./boltz_yamls
Predict affinity: yes

# ===================== 5-HT2A =====================

Protein: 5HT2A
Sequence: MDILCEENTSLSSTTNSLMQLNDDTRLYSNDFNSGEANTSDAFNWTVDSENRTNLSCEGCLSPSCLSLLHLQEKNWSALLTAVVIILTIAGNILVIMAVSLEKKLQNATNYFLMSLAIADMLLGFLVMPVSMLTILYGYRWPLPSKLCAVWIYLDVLFSTASIMHLCAISLDRYVAIQNPIHHSRFNSRTKAFLKIIAVWTISVGISMPIPVFGLQDDSKVFKEGSCLLADDNFVLIGSFVSFFIPLTIMVITYFLTIKSLQKEATLCVSDLGTRAKLASFSFLPQSSLSSEKLFQRSIHREPGSYTGRRTMQSISNEQKACKVLGIVFFLFVVMWCPFFITNIMAVICKESCNEDVIGALLNVFVWIGYLSSAVNPLVYTLFNKTYRSAFSRYIQCQYKENKKPLQLILVNTIPALAYKSSQLQMGQKKNSKQDAKTTDNDCSMVALGKQHSEEASKDNSDGVNEKVSCV
Partners: GNAQ, GNB1, GNG2
Ligands: RISP, PSIL
Apo structure: boltz_cif/H2AAP_model_0.cif
Family type: gpcr
Group: 5HT2A

Protein: H2ANG
Sequence: MDILCEENTSLSSTTNSLMQLNDDTRLYSNDFNSGEANTSDAFNWTVDSENRTNLSCEGCLSPSCLSLLHLQEKNWSALLTAVVIILTIAGNILVIMAVSLEKKLQNATNYFLMSLAIADMLLGFLVMPVSMLTILYGYRWPLPSKLCAVWIYLDVLFSTASIMHLCAISLDRYVAIQNPIHHSRFNSRTKAFLKIIAVWTISVGISMPIPVFGLQDDSKVFKEGSCLLADDNFVLIGSFVSFFIPLTIMVITYFLTIKSLQKEATLCVSDLGTRAKLASFSFLPQSSLSSEKLFQRSIHREPGSYTGRRTMQSISNEQKACKVLGIVFFLFVVMWCPFFITNIMAVICKESCNEDVIGALLNVFVWIGYLSSAVNPLVYTLFNKTYRSAFSRYIQCQYKENKKPLQLILVNTIPALAYKSSQLQMGQKKNSKQDAKTTDNDCSMVALGKQHSEEASKDNSDGVNEKVSCV
Ligands: RISP, PSIL
Apo structure: boltz_cif/H2AAP_model_0.cif
Family type: gpcr
Group: 5HT2A

Protein: H2AAP
Sequence: MDILCEENTSLSSTTNSLMQLNDDTRLYSNDFNSGEANTSDAFNWTVDSENRTNLSCEGCLSPSCLSLLHLQEKNWSALLTAVVIILTIAGNILVIMAVSLEKKLQNATNYFLMSLAIADMLLGFLVMPVSMLTILYGYRWPLPSKLCAVWIYLDVLFSTASIMHLCAISLDRYVAIQNPIHHSRFNSRTKAFLKIIAVWTISVGISMPIPVFGLQDDSKVFKEGSCLLADDNFVLIGSFVSFFIPLTIMVITYFLTIKSLQKEATLCVSDLGTRAKLASFSFLPQSSLSSEKLFQRSIHREPGSYTGRRTMQSISNEQKACKVLGIVFFLFVVMWCPFFITNIMAVICKESCNEDVIGALLNVFVWIGYLSSAVNPLVYTLFNKTYRSAFSRYIQCQYKENKKPLQLILVNTIPALAYKSSQLQMGQKKNSKQDAKTTDNDCSMVALGKQHSEEASKDNSDGVNEKVSCV
Ligands: none
Family type: gpcr
Group: 5HT2A

# ===================== 5-HT2B =====================

Protein: 5HT2B
Sequence: MALSYRVSELQSTIPEHILQSTFVHVISSNWSGLQTESIPEEMKQIVEEQGNKLHWAALLILMVIIPTIGGNTLVILAVSLEKKLQYATNYFLMSLAVADLLVGLFVMPIALLTIMFEAMWPLPLVLCPAWLFLDVLFSTASIMHLCAISVDRYIAIKKPIQANQYNSRATAFIKITVVWLISIGIAIPVPIKGIETDVDNPNNITCVLTKERFGDFMLFGSLAAFFTPLAIMIVTYFLTIHALQKKAYLVKNKPPQRLTWLTVSTVFQRDETPCSSPEKVAMLDGSRKDKALPNSGDETLMRRTSTIGKKSVQTISNEQRASKVLGIVFFLFLLMWCPFFITNITLVLCDSCNQTTLQMLLEIFVWIGYVSSGVNPLVYTLFNKTFRDAFGRYITCNYRATKSVKTLRKRSSKIYFRNPMAENSKFFKKHGIRNGINPAMYQSPMRLRSSTIQSSSIILLDTLLLTENEGDKTEEQVSYV
Partners: GNAQ, GNB1, GNG2
Ligands: BALO, LSD1
Apo structure: boltz_cif/H2BAP_model_0.cif
Family type: gpcr
Group: 5HT2B

Protein: H2BNG
Sequence: MALSYRVSELQSTIPEHILQSTFVHVISSNWSGLQTESIPEEMKQIVEEQGNKLHWAALLILMVIIPTIGGNTLVILAVSLEKKLQYATNYFLMSLAVADLLVGLFVMPIALLTIMFEAMWPLPLVLCPAWLFLDVLFSTASIMHLCAISVDRYIAIKKPIQANQYNSRATAFIKITVVWLISIGIAIPVPIKGIETDVDNPNNITCVLTKERFGDFMLFGSLAAFFTPLAIMIVTYFLTIHALQKKAYLVKNKPPQRLTWLTVSTVFQRDETPCSSPEKVAMLDGSRKDKALPNSGDETLMRRTSTIGKKSVQTISNEQRASKVLGIVFFLFLLMWCPFFITNITLVLCDSCNQTTLQMLLEIFVWIGYVSSGVNPLVYTLFNKTFRDAFGRYITCNYRATKSVKTLRKRSSKIYFRNPMAENSKFFKKHGIRNGINPAMYQSPMRLRSSTIQSSSIILLDTLLLTENEGDKTEEQVSYV
Ligands: BALO, LSD1
Apo structure: boltz_cif/H2BAP_model_0.cif
Family type: gpcr
Group: 5HT2B

Protein: H2BAP
Sequence: MALSYRVSELQSTIPEHILQSTFVHVISSNWSGLQTESIPEEMKQIVEEQGNKLHWAALLILMVIIPTIGGNTLVILAVSLEKKLQYATNYFLMSLAVADLLVGLFVMPIALLTIMFEAMWPLPLVLCPAWLFLDVLFSTASIMHLCAISVDRYIAIKKPIQANQYNSRATAFIKITVVWLISIGIAIPVPIKGIETDVDNPNNITCVLTKERFGDFMLFGSLAAFFTPLAIMIVTYFLTIHALQKKAYLVKNKPPQRLTWLTVSTVFQRDETPCSSPEKVAMLDGSRKDKALPNSGDETLMRRTSTIGKKSVQTISNEQRASKVLGIVFFLFLLMWCPFFITNITLVLCDSCNQTTLQMLLEIFVWIGYVSSGVNPLVYTLFNKTFRDAFGRYITCNYRATKSVKTLRKRSSKIYFRNPMAENSKFFKKHGIRNGINPAMYQSPMRLRSSTIQSSSIILLDTLLLTENEGDKTEEQVSYV
Ligands: none
Family type: gpcr
Group: 5HT2B

# ===================== 5-HT2C =====================

Protein: 5HT2C
Sequence: MVNLRNAVHSFLVHLIGLLVWQSDISVSPVAAIVTDIFNTSDGGRFKFPDGVQNWPALSIVIIIIMTIGGNILVIMAVSMEKKLHNATNYFLMSLAIADMLVGLLVMPLSLLAILYDYVWPLPRYLCPVWISLDVLFSTASIMHLCAISLDRYVAIRNPIEHSRFNSRTKAIMKIAIVWAISIGVSVPIPVIGLRDEEKVFVNNTTCVLNDPNFVLIGSFVAFFIPLTIMVITYCLTIYVLRRQALMLLHGHTEEPPGLSLDFLKCCKRNTAEEENSANPNQDQNARRRKKKERRPRGTMQAINNERKASKVLGIVFFVFLIMWCPFFITNILSVLCEKSCNQKLMEKLLNVFVWIGYVCSGINPLVYTLFNKIYRRAFSNYLRCNYKVEKKPPVRQIPRVAATALSGRELNVNIYRHTNEPVIEKASDNEPGIEMQVENLELPVNPSSVVSERISSV
Partners: GNAQ, GNB1, GNG2
Ligands: SB24, LORC
Apo structure: boltz_cif/H2CAP_model_0.cif
Family type: gpcr
Group: 5HT2C

Protein: H2CNG
Sequence: MVNLRNAVHSFLVHLIGLLVWQSDISVSPVAAIVTDIFNTSDGGRFKFPDGVQNWPALSIVIIIIMTIGGNILVIMAVSMEKKLHNATNYFLMSLAIADMLVGLLVMPLSLLAILYDYVWPLPRYLCPVWISLDVLFSTASIMHLCAISLDRYVAIRNPIEHSRFNSRTKAIMKIAIVWAISIGVSVPIPVIGLRDEEKVFVNNTTCVLNDPNFVLIGSFVAFFIPLTIMVITYCLTIYVLRRQALMLLHGHTEEPPGLSLDFLKCCKRNTAEEENSANPNQDQNARRRKKKERRPRGTMQAINNERKASKVLGIVFFVFLIMWCPFFITNILSVLCEKSCNQKLMEKLLNVFVWIGYVCSGINPLVYTLFNKIYRRAFSNYLRCNYKVEKKPPVRQIPRVAATALSGRELNVNIYRHTNEPVIEKASDNEPGIEMQVENLELPVNPSSVVSERISSV
Ligands: SB24, LORC
Apo structure: boltz_cif/H2CAP_model_0.cif
Family type: gpcr
Group: 5HT2C

Protein: H2CAP
Sequence: MVNLRNAVHSFLVHLIGLLVWQSDISVSPVAAIVTDIFNTSDGGRFKFPDGVQNWPALSIVIIIIMTIGGNILVIMAVSMEKKLHNATNYFLMSLAIADMLVGLLVMPLSLLAILYDYVWPLPRYLCPVWISLDVLFSTASIMHLCAISLDRYVAIRNPIEHSRFNSRTKAIMKIAIVWAISIGVSVPIPVIGLRDEEKVFVNNTTCVLNDPNFVLIGSFVAFFIPLTIMVITYCLTIYVLRRQALMLLHGHTEEPPGLSLDFLKCCKRNTAEEENSANPNQDQNARRRKKKERRPRGTMQAINNERKASKVLGIVFFVFLIMWCPFFITNILSVLCEKSCNQKLMEKLLNVFVWIGYVCSGINPLVYTLFNKIYRRAFSNYLRCNYKVEKKPPVRQIPRVAATALSGRELNVNIYRHTNEPVIEKASDNEPGIEMQVENLELPVNPSSVVSERISSV
Ligands: none
Family type: gpcr
Group: 5HT2C

# ===================== Gq heterotrimer partners =====================

Partner: GNAQ
Sequence: MTLESIMACCLSEEAKEARRINDEIERQLRRDKRDARRELKLLLLGTGESGKSTFIKQMRIIHGSGYSDEDKRGFTKLVYQNIFTAMQAMIRAMDTLKIPYKYEHNKAHAQLVREVDVEKVSAFENPYVDAIKSLWNDPGIQECYDRRREYQLSDSTKYYLNDLDRVADPAYLPTQQDVLRVRVPTTGIIEYPFDLQSVIFRMVDVGGQRSERRKWIHCFENVTSIMFLVALSEYDQVLVESDNENRMEESKALFRTIITYPWFQNSSVILFLNKKDLLEEKIMYSHLVDYFPEYDGPQRDAQAAREFILKMFVDLNPDSDKIIYSHFTCATDTENIRFVFAAVKDTILQLNLKEYNLV

Partner: GNB1
Sequence: MSELDQLRQEAEQLKNQIRDARKACADATLSQITNNIDPVGRIQMRTRRTLRGHLAKIYAMHWGTDSRLLVSASQDGKLIIWDSYTTNKVHAIPLRSSWVMTCAYAPSGNYVACGGLDNICSIYNLKTREGNVRVSRELAGHTGYLSCCRFLDDNQIVTSSGDTTCALWDIETGQQTTTFTGHTGDVMSLSLAPDTRLFVSGACDASAKLWDVREGMCRQTFTGHESDINAICFFPNGNAFATGSDDATCRLFDLRADQELMTYSHDNIICGITSVSFSKSGRLLLAGYDDFNCNVWDALKADRAGVLAGHDNRVSCLGVTDDGMAVATGSWDSFLKIWN

Partner: GNG2
Sequence: MASNNTASIAQARKLVEQLKMEANIDRIKVSKAAADLMAYCEAHAKEDPLLTPVPASENPFREKKFFCAIL

# ===================== Ligands =====================

Ligand: RISP
# Risperidone -- 5-HT2A antagonist (also broad-spectrum antipsychotic)
SMILES: CC1=C(C(=O)N2CCCCC2=N1)CCN3CCC(CC3)c4c5ccc(cc5on4)F
Role: antagonist

Ligand: PSIL
# Psilocin -- 5-HT2A agonist (active metabolite of psilocybin)
SMILES: CN(C)CCc1c[nH]c2c1c(ccc2)O
Role: agonist

Ligand: BALO
# Balovaptan -- 5-HT2B antagonist
SMILES: CN1Cc2cc(ccc2-n3c(nnc3C4CCC(CC4)Oc5ccccn5)C1)Cl
Role: antagonist

Ligand: LSD1
# LSD -- 5-HT2B agonist (also 5-HT2A)
SMILES: CCN(CC)C(=O)[C@H]1CN([C@@H]2Cc3c[nH]c4c3c(ccc4)C2=C1)C
Role: agonist

Ligand: SB24
# SB-242084 -- 5-HT2C antagonist
SMILES: Cc1cc2c(cc1Cl)N(CC2)C(=O)Nc3ccc(nc3)Oc4cccnc4C
Role: antagonist

Ligand: LORC
# Lorcaserin -- 5-HT2C agonist (former anti-obesity drug)
SMILES: C[C@H]1CNCCc2c1cc(cc2)Cl
Role: agonist