Modalities of TCR interactions with pMHCs

Introduction

In this notebook, we investigated whether TCRs can be both flexible and rigid depending on the antigen they are contacting. We also looked at the opposite phenomenon of whether peptides can be both flexible and rigid depending on the TCR that is contacting them.

[1]:

import pandas as pd

[2]:

apo_holo_summary = pd.read_csv('../data/processed/apo-holo-tcr-pmhc-class-I/apo_holo_summary.csv')
apo_holo_summary['id'] = apo_holo_summary['file_name'].str.replace('.pdb', '', regex=False)
apo_holo_summary = apo_holo_summary.set_index('id')

apo_holo_summary

[2]:

	file_name	pdb_id	structure_type	state	alpha_chain	beta_chain	antigen_chain	mhc_chain1	mhc_chain2	cdr_sequences_collated	peptide_sequence	mhc_slug
id
1ao7_D-E-C-A-B_tcr_pmhc	1ao7_D-E-C-A-B_tcr_pmhc.pdb	1ao7	tcr_pmhc	holo	D	E	C	A	B	DRGSQS-IYSNGD-AVTTDSWGKLQ-MNHEY-SVGAGI-ASRPGLA...	LLFGYPVYV	hla_a_02_01
1b0g_C-A-B_pmhc	1b0g_C-A-B_pmhc.pdb	1b0g	pmhc	apo	NaN	NaN	C	A	B	NaN	ALWGFFPVL	hla_a_02_01
1b0g_F-D-E_pmhc	1b0g_F-D-E_pmhc.pdb	1b0g	pmhc	apo	NaN	NaN	F	D	E	NaN	ALWGFFPVL	hla_a_02_01
1bd2_D-E-C-A-B_tcr_pmhc	1bd2_D-E-C-A-B_tcr_pmhc.pdb	1bd2	tcr_pmhc	holo	D	E	C	A	B	NSMFDY-ISSIKDK-AAMEGAQKLV-MNHEY-SVGAGI-ASSYPGG...	LLFGYPVYV	hla_a_02_01
1bii_P-A-B_pmhc	1bii_P-A-B_pmhc.pdb	1bii	pmhc	apo	NaN	NaN	P	A	B	NaN	RGPGRAFVTI	h2_dd
...	...	...	...	...	...	...	...	...	...	...	...	...
7rtd_C-A-B_pmhc	7rtd_C-A-B_pmhc.pdb	7rtd	pmhc	apo	NaN	NaN	C	A	B	NaN	YLQPRTFLL	hla_a_02_01
7rtr_D-E-C-A-B_tcr_pmhc	7rtr_D-E-C-A-B_tcr_pmhc.pdb	7rtr	tcr_pmhc	holo	D	E	C	A	B	DRGSQS-IYSNGD-AVNRDDKII-SEHNR-FQNEAQ-ASSPDIEQY	YLQPRTFLL	hla_a_02_01
8gvb_A-B-P-H-L_tcr_pmhc	8gvb_A-B-P-H-L_tcr_pmhc.pdb	8gvb	tcr_pmhc	holo	A	B	P	H	L	YGATPY-YFSGDTLV-AVGFTGGGNKLT-SEHNR-FQNEAQ-ASSD...	RYPLTFGW	hla_a_24_02
8gvg_A-B-P-H-L_tcr_pmhc	8gvg_A-B-P-H-L_tcr_pmhc.pdb	8gvg	tcr_pmhc	holo	A	B	P	H	L	YGATPY-YFSGDTLV-AVGFTGGGNKLT-SEHNR-FQNEAQ-ASSD...	RFPLTFGW	hla_a_24_02
8gvi_A-B-P-H-L_tcr_pmhc	8gvi_A-B-P-H-L_tcr_pmhc.pdb	8gvi	tcr_pmhc	holo	A	B	P	H	L	YGATPY-YFSGDTLV-AVVFTGGGNKLT-SEHNR-FQNEAQ-ASSL...	RYPLTFGW	hla_a_24_02

391 rows × 12 columns

[3]:

def categorize_movement(rmsd: float) -> str:
    if rmsd < 0.5:
        return f'Little Movement (<0.5 Å)'

    if 0.5 <= rmsd < 1.0:
        return f'Some Movement (0.5 to 1.0 Å)'

    if 1.0 <= rmsd < 2.0:
        return 'Movement (1.0 to 2.0 Å)'

    if 2.0 <= rmsd < 4.0:
        return 'Large Movement (2.0 to 4.0 Å)'

    if 4.0 <= rmsd:
        return 'Significant Movement (>4.0 Å)'


movement_order = pd.CategoricalDtype(categories=['Little Movement (<0.5 Å)',
                                                 'Some Movement (0.5 to 1.0 Å)',
                                                 'Movement (1.0 to 2.0 Å)',
                                                 'Large Movement (2.0 to 4.0 Å)',
                                                 'Significant Movement (>4.0 Å)'], ordered=True)

[4]:

def classify_modality(rmsd: float) -> str | None:
    return 'rigid' if rmsd < 0.5 else 'flexible' if rmsd > 1.0 else None

TCR CDR Analysis

Load data

[5]:

results_fw_align = pd.read_csv('../data/processed/apo-holo-tcr-pmhc-class-I-comparisons/rmsd_cdr_fw_align_results.csv')

results_fw_align = results_fw_align.merge(
    apo_holo_summary[['file_name',
                      'pdb_id',
                      'structure_type',
                      'state',
                      'alpha_chain',
                      'beta_chain',
                      'antigen_chain',
                      'mhc_chain1',
                      'mhc_chain2']],
    how='left',
    left_on='structure_x_name',
    right_on='file_name',
).merge(
    apo_holo_summary[['file_name',
                      'pdb_id',
                      'structure_type',
                      'state',
                      'alpha_chain',
                      'beta_chain',
                      'antigen_chain',
                      'mhc_chain1',
                      'mhc_chain2']],
    how='left',
    left_on='structure_y_name',
    right_on='file_name',
).merge(
    apo_holo_summary[['cdr_sequences_collated', 'peptide_sequence', 'mhc_slug']],
    how='left',
    left_on='complex_id',
    right_index=True,
)

[6]:

results_fw_align['comparison'] = results_fw_align['state_x'] + '-' + results_fw_align['state_y']
results_fw_align['comparison'] = results_fw_align['comparison'].map(
    lambda entry: 'apo-holo' if entry == 'holo-apo' else entry
)

results_fw_align = results_fw_align.query("comparison == 'apo-holo'").reset_index(drop=True)

[7]:

results_fw_align['structure_comparison'] = results_fw_align.apply(
    lambda row: '-'.join(sorted([row.structure_x_name, row.structure_y_name])),
    axis='columns',
)
results_fw_align = results_fw_align.drop_duplicates(['structure_comparison', 'chain_type', 'cdr']).reset_index(drop=True)

[8]:

results_fw_align

[8]:

	complex_id	structure_x_name	structure_y_name	chain_type	cdr	rmsd	file_name_x	pdb_id_x	structure_type_x	state_x	...	alpha_chain_y	beta_chain_y	antigen_chain_y	mhc_chain1_y	mhc_chain2_y	cdr_sequences_collated	peptide_sequence	mhc_slug	comparison	structure_comparison
0	3qdg_D-E-C-A-B_tcr_pmhc	3qdg_D-E-C-A-B_tcr_pmhc.pdb	3qeu_A-B_tcr.pdb	alpha_chain	1	1.932806	3qdg_D-E-C-A-B_tcr_pmhc.pdb	3qdg	tcr_pmhc	holo	...	A	B	NaN	NaN	NaN	DRGSQS-IYSNGD-AVNFGGGKLI-MRHNA-SNTAGT-ASSLSFGTEAF	ELAGIGILTV	hla_a_02_01	apo-holo	3qdg_D-E-C-A-B_tcr_pmhc.pdb-3qeu_A-B_tcr.pdb
1	3qdg_D-E-C-A-B_tcr_pmhc	3qdg_D-E-C-A-B_tcr_pmhc.pdb	3qeu_A-B_tcr.pdb	alpha_chain	2	1.308598	3qdg_D-E-C-A-B_tcr_pmhc.pdb	3qdg	tcr_pmhc	holo	...	A	B	NaN	NaN	NaN	DRGSQS-IYSNGD-AVNFGGGKLI-MRHNA-SNTAGT-ASSLSFGTEAF	ELAGIGILTV	hla_a_02_01	apo-holo	3qdg_D-E-C-A-B_tcr_pmhc.pdb-3qeu_A-B_tcr.pdb
2	3qdg_D-E-C-A-B_tcr_pmhc	3qdg_D-E-C-A-B_tcr_pmhc.pdb	3qeu_A-B_tcr.pdb	alpha_chain	3	1.244062	3qdg_D-E-C-A-B_tcr_pmhc.pdb	3qdg	tcr_pmhc	holo	...	A	B	NaN	NaN	NaN	DRGSQS-IYSNGD-AVNFGGGKLI-MRHNA-SNTAGT-ASSLSFGTEAF	ELAGIGILTV	hla_a_02_01	apo-holo	3qdg_D-E-C-A-B_tcr_pmhc.pdb-3qeu_A-B_tcr.pdb
3	3qdg_D-E-C-A-B_tcr_pmhc	3qdg_D-E-C-A-B_tcr_pmhc.pdb	3qeu_A-B_tcr.pdb	beta_chain	1	0.809066	3qdg_D-E-C-A-B_tcr_pmhc.pdb	3qdg	tcr_pmhc	holo	...	A	B	NaN	NaN	NaN	DRGSQS-IYSNGD-AVNFGGGKLI-MRHNA-SNTAGT-ASSLSFGTEAF	ELAGIGILTV	hla_a_02_01	apo-holo	3qdg_D-E-C-A-B_tcr_pmhc.pdb-3qeu_A-B_tcr.pdb
4	3qdg_D-E-C-A-B_tcr_pmhc	3qdg_D-E-C-A-B_tcr_pmhc.pdb	3qeu_A-B_tcr.pdb	beta_chain	2	0.688597	3qdg_D-E-C-A-B_tcr_pmhc.pdb	3qdg	tcr_pmhc	holo	...	A	B	NaN	NaN	NaN	DRGSQS-IYSNGD-AVNFGGGKLI-MRHNA-SNTAGT-ASSLSFGTEAF	ELAGIGILTV	hla_a_02_01	apo-holo	3qdg_D-E-C-A-B_tcr_pmhc.pdb-3qeu_A-B_tcr.pdb
...	...	...	...	...	...	...	...	...	...	...	...	...	...	...	...	...	...	...	...	...	...
569	7rtr_D-E-C-A-B_tcr_pmhc	7n1d_A-B_tcr.pdb	7rtr_D-E-C-A-B_tcr_pmhc.pdb	alpha_chain	2	0.810170	7n1d_A-B_tcr.pdb	7n1d	tcr	apo	...	D	E	C	A	B	DRGSQS-IYSNGD-AVNRDDKII-SEHNR-FQNEAQ-ASSPDIEQY	YLQPRTFLL	hla_a_02_01	apo-holo	7n1d_A-B_tcr.pdb-7rtr_D-E-C-A-B_tcr_pmhc.pdb
570	7rtr_D-E-C-A-B_tcr_pmhc	7n1d_A-B_tcr.pdb	7rtr_D-E-C-A-B_tcr_pmhc.pdb	alpha_chain	3	0.563263	7n1d_A-B_tcr.pdb	7n1d	tcr	apo	...	D	E	C	A	B	DRGSQS-IYSNGD-AVNRDDKII-SEHNR-FQNEAQ-ASSPDIEQY	YLQPRTFLL	hla_a_02_01	apo-holo	7n1d_A-B_tcr.pdb-7rtr_D-E-C-A-B_tcr_pmhc.pdb
571	7rtr_D-E-C-A-B_tcr_pmhc	7n1d_A-B_tcr.pdb	7rtr_D-E-C-A-B_tcr_pmhc.pdb	beta_chain	1	0.399182	7n1d_A-B_tcr.pdb	7n1d	tcr	apo	...	D	E	C	A	B	DRGSQS-IYSNGD-AVNRDDKII-SEHNR-FQNEAQ-ASSPDIEQY	YLQPRTFLL	hla_a_02_01	apo-holo	7n1d_A-B_tcr.pdb-7rtr_D-E-C-A-B_tcr_pmhc.pdb
572	7rtr_D-E-C-A-B_tcr_pmhc	7n1d_A-B_tcr.pdb	7rtr_D-E-C-A-B_tcr_pmhc.pdb	beta_chain	2	0.284455	7n1d_A-B_tcr.pdb	7n1d	tcr	apo	...	D	E	C	A	B	DRGSQS-IYSNGD-AVNRDDKII-SEHNR-FQNEAQ-ASSPDIEQY	YLQPRTFLL	hla_a_02_01	apo-holo	7n1d_A-B_tcr.pdb-7rtr_D-E-C-A-B_tcr_pmhc.pdb
573	7rtr_D-E-C-A-B_tcr_pmhc	7n1d_A-B_tcr.pdb	7rtr_D-E-C-A-B_tcr_pmhc.pdb	beta_chain	3	0.432453	7n1d_A-B_tcr.pdb	7n1d	tcr	apo	...	D	E	C	A	B	DRGSQS-IYSNGD-AVNRDDKII-SEHNR-FQNEAQ-ASSPDIEQY	YLQPRTFLL	hla_a_02_01	apo-holo	7n1d_A-B_tcr.pdb-7rtr_D-E-C-A-B_tcr_pmhc.pdb

574 rows × 29 columns

Analysis

[9]:

def average_and_classify_cdr_movement(group):
    group_mean = group.groupby(['chain_type',
                                'cdr',
                                'peptide_sequence',
                                'mhc_slug']).agg({'rmsd': 'mean'})
    group_mean['movement'] = group_mean['rmsd'].map(categorize_movement).astype(movement_order)
    group_mean['classification'] = group_mean['rmsd'].map(classify_modality)

    return group_mean

cdr_results_agg = (results_fw_align.groupby('cdr_sequences_collated')
                                   .apply(average_and_classify_cdr_movement)
                                   .reset_index())

[10]:

cdr_results_agg_multi_pmhc = (cdr_results_agg.groupby(['cdr_sequences_collated', 'chain_type', 'cdr'])
                                             .filter(lambda group: len(group) > 1))

[11]:

cdr_results_agg_multi_pmhc['num_modalities'] = (
    cdr_results_agg_multi_pmhc.groupby(['cdr_sequences_collated', 'chain_type', 'cdr'])['classification']
                              .transform(lambda movement: movement.nunique())
)

[12]:

cdr_results_agg_multi_pmhc

[12]:

	cdr_sequences_collated	chain_type	cdr	peptide_sequence	mhc_slug	rmsd	movement	classification	num_modalities
11	DRGSQS-IYSNGD-AVNFGGGKLI-MRHNA-SNTAGT-ASSLSFGTEAF	alpha_chain	1	AAGIGILTV	hla_a_02_01	2.149292	Large Movement (2.0 to 4.0 Å)	flexible	1
12	DRGSQS-IYSNGD-AVNFGGGKLI-MRHNA-SNTAGT-ASSLSFGTEAF	alpha_chain	1	ELAGIGILTV	hla_a_02_01	2.188011	Large Movement (2.0 to 4.0 Å)	flexible	1
13	DRGSQS-IYSNGD-AVNFGGGKLI-MRHNA-SNTAGT-ASSLSFGTEAF	alpha_chain	1	MMWDRGLGMM	hla_a_02_01	1.983439	Movement (1.0 to 2.0 Å)	flexible	1
14	DRGSQS-IYSNGD-AVNFGGGKLI-MRHNA-SNTAGT-ASSLSFGTEAF	alpha_chain	1	SMLGIGIVPV	hla_a_02_01	2.269887	Large Movement (2.0 to 4.0 Å)	flexible	1
15	DRGSQS-IYSNGD-AVNFGGGKLI-MRHNA-SNTAGT-ASSLSFGTEAF	alpha_chain	2	AAGIGILTV	hla_a_02_01	1.095455	Movement (1.0 to 2.0 Å)	flexible	1
...	...	...	...	...	...	...	...	...	...
287	YSATPY-YYSGDPVV-AVSGFASALT-NNHNN-SYGAGS-ASGGGGTLY	beta_chain	1	SIYRYYGL	h2_kb	0.579553	Some Movement (0.5 to 1.0 Å)	None	0
288	YSATPY-YYSGDPVV-AVSGFASALT-NNHNN-SYGAGS-ASGGGGTLY	beta_chain	2	EQYKFYSV	h2_kb	0.850569	Some Movement (0.5 to 1.0 Å)	None	0
289	YSATPY-YYSGDPVV-AVSGFASALT-NNHNN-SYGAGS-ASGGGGTLY	beta_chain	2	SIYRYYGL	h2_kb	0.938313	Some Movement (0.5 to 1.0 Å)	None	0
290	YSATPY-YYSGDPVV-AVSGFASALT-NNHNN-SYGAGS-ASGGGGTLY	beta_chain	3	EQYKFYSV	h2_kb	1.084084	Movement (1.0 to 2.0 Å)	flexible	1
291	YSATPY-YYSGDPVV-AVSGFASALT-NNHNN-SYGAGS-ASGGGGTLY	beta_chain	3	SIYRYYGL	h2_kb	0.925296	Some Movement (0.5 to 1.0 Å)	None	1

226 rows × 9 columns

[13]:

cdr_results_agg_multi_pmhc['num_modalities'].describe()

[13]:

count    226.000000
mean       0.814159
std        0.389842
min        0.000000
25%        1.000000
50%        1.000000
75%        1.000000
max        1.000000
Name: num_modalities, dtype: float64

[14]:

cdr_results_agg_multi_pmhc.query('num_modalities > 1')

[14]:

	cdr_sequences_collated	chain_type	cdr	peptide_sequence	mhc_slug	rmsd	movement	classification	num_modalities

No TCRs had both <0.5 Å RMSD movement binding to one antigen and >1.0 Å RMSD binding to a different antigen.

Peptide Analysis

Load data

[15]:

pmhc_results = pd.read_csv('../data/processed/apo-holo-tcr-pmhc-class-I-comparisons/pmhc_tcr_contact_apo_holo.csv')

peptide_results = pmhc_results.query("chain_type == 'antigen_chain'").reset_index(drop=True)
peptide_results = peptide_results.drop(columns=['chain_type', 'tcr_contact'])

peptide_results = peptide_results.merge(
    apo_holo_summary[['file_name',
                      'pdb_id',
                      'structure_type',
                      'state',
                      'alpha_chain',
                      'beta_chain',
                      'antigen_chain',
                      'mhc_chain1',
                      'mhc_chain2']],
    how='left',
    left_on='structure_x_name',
    right_on='file_name',
).merge(
    apo_holo_summary[['file_name',
                      'pdb_id',
                      'structure_type',
                      'state',
                      'alpha_chain',
                      'beta_chain',
                      'antigen_chain',
                      'mhc_chain1',
                      'mhc_chain2']],
    how='left',
    left_on='structure_y_name',
    right_on='file_name',
).merge(
    apo_holo_summary[['cdr_sequences_collated', 'peptide_sequence', 'mhc_slug']],
    how='left',
    left_on='complex_id',
    right_index=True,
)

[16]:

peptide_results['comparison'] = peptide_results['state_x'] + '-' + peptide_results['state_y']
peptide_results['comparison'] = peptide_results['comparison'].map(
    lambda entry: 'apo-holo' if entry == 'holo-apo' else entry
)

peptide_results = peptide_results.query("comparison == 'apo-holo'").reset_index(drop=True)

[17]:

peptide_results['structure_comparison'] = peptide_results.apply(
    lambda row: '-'.join(sorted([row.structure_x_name, row.structure_y_name])),
    axis='columns',
)
peptide_results = peptide_results.drop_duplicates(['structure_comparison']).reset_index(drop=True)

[18]:

peptide_results

[18]:

	complex_id	structure_x_name	structure_y_name	rmsd	file_name_x	pdb_id_x	structure_type_x	state_x	alpha_chain_x	beta_chain_x	...	alpha_chain_y	beta_chain_y	antigen_chain_y	mhc_chain1_y	mhc_chain2_y	cdr_sequences_collated	peptide_sequence	mhc_slug	comparison	structure_comparison
0	5c0a_D-E-C-A-B_tcr_pmhc	5c0a_D-E-C-A-B_tcr_pmhc.pdb	5n1y_C-A-B_pmhc.pdb	0.448858	5c0a_D-E-C-A-B_tcr_pmhc.pdb	5c0a	tcr_pmhc	holo	D	E	...	NaN	NaN	C	A	B	NSAFQY-TYSSGN-AMRGDSSYKLI-SGHDY-FNNNVP-ASSLWEK...	MVWGPDPLYV	hla_a_02_01	apo-holo	5c0a_D-E-C-A-B_tcr_pmhc.pdb-5n1y_C-A-B_pmhc.pdb
1	5wlg_D-E-C-A-B_tcr_pmhc	5wlg_D-E-C-A-B_tcr_pmhc.pdb	5wli_C-A-B_pmhc.pdb	0.498148	5wlg_D-E-C-A-B_tcr_pmhc.pdb	5wlg	tcr_pmhc	holo	D	E	...	NaN	NaN	C	A	B	TYTTV-IRSNERE-ATVYAQGLT-NNHDY-SYVADS-ASSDWGDTGQLY	SQLLNAKYL	h2_db	apo-holo	5wlg_D-E-C-A-B_tcr_pmhc.pdb-5wli_C-A-B_pmhc.pdb
2	5wlg_D-E-C-A-B_tcr_pmhc	5wlg_D-E-C-A-B_tcr_pmhc.pdb	5wli_F-D-E_pmhc.pdb	0.519507	5wlg_D-E-C-A-B_tcr_pmhc.pdb	5wlg	tcr_pmhc	holo	D	E	...	NaN	NaN	F	D	E	TYTTV-IRSNERE-ATVYAQGLT-NNHDY-SYVADS-ASSDWGDTGQLY	SQLLNAKYL	h2_db	apo-holo	5wlg_D-E-C-A-B_tcr_pmhc.pdb-5wli_F-D-E_pmhc.pdb
3	5wlg_D-E-C-A-B_tcr_pmhc	5wlg_D-E-C-A-B_tcr_pmhc.pdb	5wli_I-G-H_pmhc.pdb	0.459025	5wlg_D-E-C-A-B_tcr_pmhc.pdb	5wlg	tcr_pmhc	holo	D	E	...	NaN	NaN	I	G	H	TYTTV-IRSNERE-ATVYAQGLT-NNHDY-SYVADS-ASSDWGDTGQLY	SQLLNAKYL	h2_db	apo-holo	5wlg_D-E-C-A-B_tcr_pmhc.pdb-5wli_I-G-H_pmhc.pdb
4	5wlg_D-E-C-A-B_tcr_pmhc	5wlg_D-E-C-A-B_tcr_pmhc.pdb	5wli_L-J-K_pmhc.pdb	0.494705	5wlg_D-E-C-A-B_tcr_pmhc.pdb	5wlg	tcr_pmhc	holo	D	E	...	NaN	NaN	L	J	K	TYTTV-IRSNERE-ATVYAQGLT-NNHDY-SYVADS-ASSDWGDTGQLY	SQLLNAKYL	h2_db	apo-holo	5wlg_D-E-C-A-B_tcr_pmhc.pdb-5wli_L-J-K_pmhc.pdb
...	...	...	...	...	...	...	...	...	...	...	...	...	...	...	...	...	...	...	...	...	...
372	7rtr_D-E-C-A-B_tcr_pmhc	7n6d_G-E-F_pmhc.pdb	7rtr_D-E-C-A-B_tcr_pmhc.pdb	0.468869	7n6d_G-E-F_pmhc.pdb	7n6d	pmhc	apo	NaN	NaN	...	D	E	C	A	B	DRGSQS-IYSNGD-AVNRDDKII-SEHNR-FQNEAQ-ASSPDIEQY	YLQPRTFLL	hla_a_02_01	apo-holo	7n6d_G-E-F_pmhc.pdb-7rtr_D-E-C-A-B_tcr_pmhc.pdb
373	7rtr_D-E-C-A-B_tcr_pmhc	7n6d_K-I-J_pmhc.pdb	7rtr_D-E-C-A-B_tcr_pmhc.pdb	0.411050	7n6d_K-I-J_pmhc.pdb	7n6d	pmhc	apo	NaN	NaN	...	D	E	C	A	B	DRGSQS-IYSNGD-AVNRDDKII-SEHNR-FQNEAQ-ASSPDIEQY	YLQPRTFLL	hla_a_02_01	apo-holo	7n6d_K-I-J_pmhc.pdb-7rtr_D-E-C-A-B_tcr_pmhc.pdb
374	7rtr_D-E-C-A-B_tcr_pmhc	7n6d_O-M-N_pmhc.pdb	7rtr_D-E-C-A-B_tcr_pmhc.pdb	0.448905	7n6d_O-M-N_pmhc.pdb	7n6d	pmhc	apo	NaN	NaN	...	D	E	C	A	B	DRGSQS-IYSNGD-AVNRDDKII-SEHNR-FQNEAQ-ASSPDIEQY	YLQPRTFLL	hla_a_02_01	apo-holo	7n6d_O-M-N_pmhc.pdb-7rtr_D-E-C-A-B_tcr_pmhc.pdb
375	7rtr_D-E-C-A-B_tcr_pmhc	7p3d_C-A-B_pmhc.pdb	7rtr_D-E-C-A-B_tcr_pmhc.pdb	0.765295	7p3d_C-A-B_pmhc.pdb	7p3d	pmhc	apo	NaN	NaN	...	D	E	C	A	B	DRGSQS-IYSNGD-AVNRDDKII-SEHNR-FQNEAQ-ASSPDIEQY	YLQPRTFLL	hla_a_02_01	apo-holo	7p3d_C-A-B_pmhc.pdb-7rtr_D-E-C-A-B_tcr_pmhc.pdb
376	7rtr_D-E-C-A-B_tcr_pmhc	7rtd_C-A-B_pmhc.pdb	7rtr_D-E-C-A-B_tcr_pmhc.pdb	0.455078	7rtd_C-A-B_pmhc.pdb	7rtd	pmhc	apo	NaN	NaN	...	D	E	C	A	B	DRGSQS-IYSNGD-AVNRDDKII-SEHNR-FQNEAQ-ASSPDIEQY	YLQPRTFLL	hla_a_02_01	apo-holo	7rtd_C-A-B_pmhc.pdb-7rtr_D-E-C-A-B_tcr_pmhc.pdb

377 rows × 27 columns

Analysis

[19]:

def average_and_classify_peptide_movement(group):
    group_mean = group.groupby('cdr_sequences_collated').agg({'rmsd': 'mean'})
    group_mean['movement'] = group_mean['rmsd'].map(categorize_movement).astype(movement_order)
    group_mean['classification'] = group_mean['rmsd'].map(classify_modality)

    return group_mean

peptide_results_agg = (peptide_results.groupby(['peptide_sequence', 'mhc_slug'])
                                      .apply(average_and_classify_peptide_movement)
                                      .reset_index())

[20]:

peptide_results_agg_multi_tcr = (peptide_results_agg.groupby(['mhc_slug', 'peptide_sequence'])
                                                    .filter(lambda group: len(group) > 1))

[21]:

peptide_results_agg_multi_tcr['num_modalities'] = (
    peptide_results_agg_multi_tcr.groupby(['mhc_slug', 'peptide_sequence'])['classification']
                                 .transform(lambda movement: movement.nunique())
)

[22]:

peptide_results_agg_multi_tcr

[22]:

	peptide_sequence	mhc_slug	cdr_sequences_collated	rmsd	movement	classification	num_modalities
0	AAGIGILTV	hla_a_02_01	DRGSQS-IYSNGD-AVNFGGGKLI-MRHNA-SNTAGT-ASSLSFGTEAF	1.157017	Movement (1.0 to 2.0 Å)	flexible	1
1	AAGIGILTV	hla_a_02_01	DRGSQS-IYSNGD-AVNVAGKST-GTSNPN-SVGIG-AWSETGLGT...	1.134248	Movement (1.0 to 2.0 Å)	flexible	1
2	AAGIGILTV	hla_a_02_01	FLGSQS-TYREGD-AVNDGGRLT-GTSNPN-WGPFG-AWSETGLGM...	0.986466	Some Movement (0.5 to 1.0 Å)	None	1
3	AAGIGILTV	hla_a_02_01	SIFNT-LYKAGEL-AGGTGNQFY-ENHRY-SYGVKD-AISEVGVGQPQH	1.323428	Movement (1.0 to 2.0 Å)	flexible	1
4	AAGIGILTV	hla_a_02_01	YRGSQS-IYSNGD-AVNFGGGKLI-MRHNA-SNTAGT-ASSWSFGTEAF	0.526953	Some Movement (0.5 to 1.0 Å)	None	1
8	APRGPHGGAASGL	hla_b_07_02	NIATNDY-GYKTK-LVGEILDNFNKFY-MDHEN-SYDVKM-ASSQR...	4.232887	Significant Movement (>4.0 Å)	flexible	1
9	APRGPHGGAASGL	hla_b_07_02	NIATNDY-GYKTK-LVVDQKLV-SGDLS-YYNGEE-ASSGGHTGSNEQF	2.814299	Large Movement (2.0 to 4.0 Å)	flexible	1
11	ASNENMETM	h2_db	DSTFNY-IRSVSDK-AASEGSGSWQLI-MNHDT-YYDKIL-ASSAG...	0.396101	Little Movement (<0.5 Å)	rigid	1
12	ASNENMETM	h2_db	DSTFNY-IRSVSDK-AASETSGSWQLI-MNHDT-YYDKIL-ASSRD...	0.409245	Little Movement (<0.5 Å)	rigid	1
13	ASNENMETM	h2_db	TTMRS-LASGT-AAVTGNTGKLI-MNHDT-YYDKIL-ASSRGTIHS...	0.558530	Some Movement (0.5 to 1.0 Å)	None	1
14	EAAGIGILTV	hla_a_02_01	DRGSQS-IYSNGD-AVNVAGKST-GTSNPN-SVGIG-AWSETGLGT...	3.621428	Large Movement (2.0 to 4.0 Å)	flexible	1
15	EAAGIGILTV	hla_a_02_01	FLGSQS-TYREGD-AVNDGGRLT-GTSNPN-WGPFG-AWSETGLGM...	3.573235	Large Movement (2.0 to 4.0 Å)	flexible	1
22	FLRGRAYGL	hla_b_08_01	NSASQS-VYSSG-VVRAGKLI-MNHEY-SVGEGT-ASGQGNFDIQY	0.617307	Some Movement (0.5 to 1.0 Å)	None	0
23	FLRGRAYGL	hla_b_08_01	TISGTDY-GLTSN-ILPLAGGTSYGKLT-SGHVS-FQNEAQ-ASSL...	0.717857	Some Movement (0.5 to 1.0 Å)	None	0
24	FLRGRAYGL	hla_b_08_01	TSDPSYG-QGSYDQGN-AMREDTGNQFY-SGHAT-FQNNGV-ASSF...	0.596415	Some Movement (0.5 to 1.0 Å)	None	0
27	GILGFVFTL	hla_a_02_01	SSNFYA-MTLNGDE-AFDTNAGKST-LNHDA-SQIVND-ASSIFGQ...	0.446045	Little Movement (<0.5 Å)	rigid	1
28	GILGFVFTL	hla_a_02_01	SVFSS-VVTGGEV-AGAGSQGNLI-LNHDA-SQIVND-ASSSRASYEQY	0.581065	Some Movement (0.5 to 1.0 Å)	None	1
29	GILGFVFTL	hla_a_02_01	SVFSS-VVTGGEV-AGAGSQGNLI-LNHDA-SQIVND-ASSSRSSYEQY	0.465703	Little Movement (<0.5 Å)	rigid	1
30	GILGFVFTL	hla_a_02_01	SVFSS-VVTGGEV-AGAIGPSNTGKLI-LNHDA-SQIVND-ASSIR...	0.344910	Little Movement (<0.5 Å)	rigid	1
31	GILGFVFTL	hla_a_02_01	TSESDYY-QEAYKQQN-AWGVNAGGTSYGKLT-LNHDA-SQIVND-...	0.564845	Some Movement (0.5 to 1.0 Å)	None	1
37	HMTEVVRHC	hla_a_02_01	NSAFQY-TYSSGN-AMSGLKEDSSYKLI-MNHEY-SMNVEV-ASSI...	0.694367	Some Movement (0.5 to 1.0 Å)	None	0
38	HMTEVVRHC	hla_a_02_01	NSASQS-VYSSG-VVQPGGYQKVT-MNHNS-SASEGT-ASSEGLWQ...	0.785581	Some Movement (0.5 to 1.0 Å)	None	0
39	HMTEVVRHC	hla_a_02_01	NYSPAY-IRENEKE-ALDIYPHDMR-SGHAT-FQNNGV-ASSLDPG...	0.864221	Some Movement (0.5 to 1.0 Å)	None	0
40	HMTEVVRHC	hla_a_02_01	TSENNYY-QEAYK-AFMGYSGAGSYQLT-ENHRY-SYGVKD-AISE...	0.809779	Some Movement (0.5 to 1.0 Å)	None	0
45	IPLTEEAEL	hla_b_35_01	TRDTTYY-RNSFDEQN-ALSHNSGGSNYKLT-SGHNT-YYREEE-A...	1.013667	Movement (1.0 to 2.0 Å)	flexible	1
46	IPLTEEAEL	hla_b_35_01	TSWWSYY-QGSDEQN-ALGEGGAQKLV-MNHNS-SASEGT-ASRTR...	1.104902	Movement (1.0 to 2.0 Å)	flexible	1
58	LLFGYPVYV	hla_a_02_01	DRGSQS-IYSNGD-AVTTDSWGKLQ-MNHEY-SVGAGI-ASRPGLA...	1.071247	Movement (1.0 to 2.0 Å)	flexible	1
59	LLFGYPVYV	hla_a_02_01	DRGSQS-IYSNGD-AVTTDSWGKLQ-MNHEY-SVGAGI-ASRPGLM...	1.084802	Movement (1.0 to 2.0 Å)	flexible	1
60	LLFGYPVYV	hla_a_02_01	IRSSTS-IYSNGD-AVTTDRSGKLQ-MNHEY-SVGVGI-ASRPGAA...	0.659812	Some Movement (0.5 to 1.0 Å)	None	1
61	LLFGYPVYV	hla_a_02_01	NSMFDY-ISSIKDK-AAMEGAQKLV-MNHEY-SVGAGI-ASSYPGG...	1.105653	Movement (1.0 to 2.0 Å)	flexible	1
63	LPEPLPQGQLTAY	hla_b_35_08	TRDTTYY-RNSFDEQN-ALSGFYNTDKLI-MNHNS-SASEGT-ASP...	0.467122	Little Movement (<0.5 Å)	rigid	1
64	LPEPLPQGQLTAY	hla_b_35_08	TRDTTYY-RNSFDEQN-ALSGFYNTDKLI-MNHNS-SASEGT-ASP...	0.450190	Little Movement (<0.5 Å)	rigid	1
65	LPEPLPQGQLTAY	hla_b_35_08	TTSDR-LLSNGAV-AVGGGSNYQLI-SGHDT-YYEEEE-ASSRTGS...	0.781614	Some Movement (0.5 to 1.0 Å)	None	1
69	NLVPMVATV	hla_a_02_01	SSNFYA-MTLNGDE-ARNTGNQFY-MNHEY-SVGAGI-ASSPVTGG...	0.569056	Some Movement (0.5 to 1.0 Å)	None	0
70	NLVPMVATV	hla_a_02_01	TISGTDY-GLTSN-ILDNNNDMR-SGHVS-FNYEAQ-ASSLAPGTT...	0.717804	Some Movement (0.5 to 1.0 Å)	None	0
74	RFPLTFGWCF	hla_a_24_02	DRGSQS-IYSNGD-GTYNQGGKLI-MNHEY-SMNVEV-ASSGASHEQY	1.302746	Movement (1.0 to 2.0 Å)	flexible	1
75	RFPLTFGWCF	hla_a_24_02	YGATPY-YFSGDTLV-AVGAPSGAGSYQLT-MGHRA-YSYEKL-AS...	0.830768	Some Movement (0.5 to 1.0 Å)	None	1
85	RYPLTFGW	hla_a_24_02	YGATPY-YFSGDTLV-AVGFTGGGNKLT-SEHNR-FQNEAQ-ASSD...	0.869939	Some Movement (0.5 to 1.0 Å)	None	0
86	RYPLTFGW	hla_a_24_02	YGATPY-YFSGDTLV-AVVFTGGGNKLT-SEHNR-FQNEAQ-ASSL...	0.708066	Some Movement (0.5 to 1.0 Å)	None	0
87	RYPLTFGWCF	hla_a_24_02	DSAIYN-IQSSQRE-AVRMDSSYKLI-SEHNR-FQNEAQ-ASSSWD...	1.522271	Movement (1.0 to 2.0 Å)	flexible	1
88	RYPLTFGWCF	hla_a_24_02	TSWWSYY-QGSDEQN-ALGELARSGGYQKVT-GTSNPN-SVGIG-A...	1.112057	Movement (1.0 to 2.0 Å)	flexible	1
91	SLLMWITQC	hla_a_02_01	DSAIYN-IPFWQRE-AVRPTSGGSYIPT-MNHEY-SVSVGM-ASSY...	0.972491	Some Movement (0.5 to 1.0 Å)	None	0
92	SLLMWITQC	hla_a_02_01	DSAIYN-IQSSQRE-AVRPLLDGTYIPT-MNHEY-SVGAGT-ASSY...	0.875077	Some Movement (0.5 to 1.0 Å)	None	0
93	SLLMWITQC	hla_a_02_01	DSAIYN-IQSSQRE-AVRPTSGGSYIPT-MNHEY-SVGAGI-ASSY...	0.880234	Some Movement (0.5 to 1.0 Å)	None	0
94	SLLMWITQC	hla_a_02_01	DSAIYN-ITPWQRE-AVRPLLDGTYIPT-MNHEY-SVAIQT-ASSY...	0.826961	Some Movement (0.5 to 1.0 Å)	None	0
95	SLLMWITQC	hla_a_02_01	DSAIYN-ITPWQRE-AVRPLLDGTYIPT-MNHEY-SVSVGM-ASSY...	0.839051	Some Movement (0.5 to 1.0 Å)	None	0
100	SSLCNFRAYV	h2_db	TISGNEY-GLQQN-ILSGGCNYKLT-MSHET-SYDVDS-ASSFGREQY	0.344040	Little Movement (<0.5 Å)	rigid	1
101	SSLCNFRAYV	h2_db	TISGNEY-GLQQN-ILSGGSNYKLT-MSHET-SYDVDS-ASSFGREQY	0.356701	Little Movement (<0.5 Å)	rigid	1
106	VVVGADGVGK	hla_a_11_01	TRDTAYY-QPWWGEQN-AMSVPSGDGSYQFT-MNHEY-SVGEGT-A...	1.256482	Movement (1.0 to 2.0 Å)	flexible	1
107	VVVGADGVGK	hla_a_11_01	TRDTTYY-RNSFDEQN-ALSGPSGAGSYQLT-MNHEY-SVGEGT-A...	1.259841	Movement (1.0 to 2.0 Å)	flexible	1
111	YLQPRTFLL	hla_a_02_01	DRGSQS-IYSNGD-AVNRDDKII-SEHNR-FQNEAQ-ASSPDIEQY	0.512357	Some Movement (0.5 to 1.0 Å)	None	0
112	YLQPRTFLL	hla_a_02_01	NSASQS-VYSSG-VVNINTDKLI-SEHNR-FQNEAQ-ASSSANSGELF	0.627788	Some Movement (0.5 to 1.0 Å)	None	0
113	YLQPRTFLL	hla_a_02_01	NSASQS-VYSSG-VVNRNNDMR-LNHDA-SQIVND-AGQVTNTGELF	0.685808	Some Movement (0.5 to 1.0 Å)	None	0

[23]:

peptide_results_agg_multi_tcr['num_modalities'].describe()

[23]:

count    53.000000
mean      0.641509
std       0.484146
min       0.000000
25%       0.000000
50%       1.000000
75%       1.000000
max       1.000000
Name: num_modalities, dtype: float64

[24]:

peptide_results_agg_multi_tcr.query('num_modalities > 1')

[24]:

	peptide_sequence	mhc_slug	cdr_sequences_collated	rmsd	movement	classification	num_modalities

Similarly, no peptides have both large (>1.0 Å RMSD) conformational changes and small (<0.5 Å RMSD) conformational changes for different TCRs.

Conclusion

Neither the TCR CDR loops, nor the peptides show different movement modalities (rigid vs flexible) when contacted by different entities. These results indicate that the flexiblity of TCRs between apo and holo conformations is dependent on the composition of the entitity itself and not the entitity it is contacting.