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import os
import gradio as gr
import re
import pandas as pd
from io import StringIO
import rdkit
from rdkit import Chem
from rdkit.Chem import AllChem, Draw
import numpy as np
from PIL import Image, ImageDraw, ImageFont
import matplotlib.pyplot as plt
import matplotlib.patches as patches
from io import BytesIO
import tempfile
from rdkit import Chem

class PeptideAnalyzer:
    def __init__(self):
        self.bond_patterns = [
            (r'OC\(=O\)', 'ester'),  # Ester bond
            (r'N\(C\)C\(=O\)', 'n_methyl'),  # N-methylated peptide bond
            (r'N[0-9]C\(=O\)', 'proline'),  # Proline peptide bond
            (r'NC\(=O\)', 'peptide'),  # Standard peptide bond
            (r'C\(=O\)N\(C\)', 'n_methyl_reverse'),  # Reverse N-methylated
            (r'C\(=O\)N[12]?', 'peptide_reverse')  # Reverse peptide bond
        ]
        # Three to one letter code mapping
        self.three_to_one = {
            'Ala': 'A', 'Cys': 'C', 'Asp': 'D', 'Glu': 'E',
            'Phe': 'F', 'Gly': 'G', 'His': 'H', 'Ile': 'I',
            'Lys': 'K', 'Leu': 'L', 'Met': 'M', 'Asn': 'N',
            'Pro': 'P', 'Gln': 'Q', 'Arg': 'R', 'Ser': 'S',
            'Thr': 'T', 'Val': 'V', 'Trp': 'W', 'Tyr': 'Y'
        }
    
    def is_peptide(self, smiles):
        """Check if the SMILES represents a peptide structure"""
        mol = Chem.MolFromSmiles(smiles)
        if mol is None:
            return False
            
        # Look for peptide bonds: NC(=O) pattern
        peptide_bond_pattern = Chem.MolFromSmarts('[NH][C](=O)')
        if mol.HasSubstructMatch(peptide_bond_pattern):
            return True
            
        # Look for N-methylated peptide bonds: N(C)C(=O) pattern
        n_methyl_pattern = Chem.MolFromSmarts('[N;H0;$(NC)](C)[C](=O)')
        if mol.HasSubstructMatch(n_methyl_pattern):
            return True
        
        return False

    def is_cyclic(self, smiles):
        """Improved cyclic peptide detection"""
        # Check for C-terminal carboxyl
        if smiles.endswith('C(=O)O'):
            return False, [], []
            
        # Find all numbers used in ring closures
        ring_numbers = re.findall(r'(?:^|[^c])[0-9](?=[A-Z@\(\)])', smiles)
        
        # Find aromatic ring numbers
        aromatic_matches = re.findall(r'c[0-9](?:ccccc|c\[nH\]c)[0-9]', smiles)
        aromatic_cycles = []
        for match in aromatic_matches:
            numbers = re.findall(r'[0-9]', match)
            aromatic_cycles.extend(numbers)
        
        # Numbers that aren't part of aromatic rings are peptide cycles
        peptide_cycles = [n for n in ring_numbers if n not in aromatic_cycles]
        
        is_cyclic = len(peptide_cycles) > 0 and not smiles.endswith('C(=O)O')
        return is_cyclic, peptide_cycles, aromatic_cycles
       
    def split_on_bonds(self, smiles):
        positions = []
        used = set()
        # Find Gly pattern first
        gly_pattern = r'NCC\(=O\)'
        for match in re.finditer(gly_pattern, smiles):
            if not any(p in range(match.start(), match.end()) for p in used):
                positions.append({
                    'start': match.start(),
                    'end': match.end(),
                    'type': 'gly',
                    'pattern': match.group()
                })
                used.update(range(match.start(), match.end()))
        
        for pattern, bond_type in self.bond_patterns:
            for match in re.finditer(pattern, smiles):
                if not any(p in range(match.start(), match.end()) for p in used):
                    positions.append({
                        'start': match.start(),
                        'end': match.end(),
                        'type': bond_type,
                        'pattern': match.group()
                    })
                    used.update(range(match.start(), match.end()))

        # Sort by position
        positions.sort(key=lambda x: x['start'])
        
        # Create segments
        segments = []
        if positions:
            # First segment
            if positions[0]['start'] > 0:
                segments.append({
                    'content': smiles[0:positions[0]['start']],
                    'bond_after': positions[0]['pattern']
                })
            # Process segments
            for i in range(len(positions)-1):
                current = positions[i]
                next_pos = positions[i+1]
                if current['type'] == 'gly':
                    segments.append({
                        'content': 'NCC(=O)',
                        'bond_before': positions[i-1]['pattern'] if i > 0 else None,
                        'bond_after': next_pos['pattern']
                    })
                    segments.append({
                        'content': smiles[current['start']+7:next_pos['start']],
                        'bond_before': 'gly_bond',
                        'bond_after': next_pos['pattern']
                    })
                else:
                    content = smiles[current['end']:next_pos['start']]
                    if content:
                        segments.append({
                            'content': content,
                            'bond_before': current['pattern'],
                            'bond_after': next_pos['pattern']
                        })
            
            # Last segment
            if positions[-1]['end'] < len(smiles):
                segments.append({
                    'content': smiles[positions[-1]['end']:],
                    'bond_before': positions[-1]['pattern']
                })
        return segments

    def clean_terminal_carboxyl(self, segment):
        """Remove C-terminal carboxyl only if it's the true terminus"""
        content = segment['content']
        
        # Only clean if:
        # 1. Contains C(=O)O
        # 2. No bond_after exists (meaning it's the last segment)
        # 3. C(=O)O is at the end of the content
        if 'C(=O)O' in content and not segment.get('bond_after'):
            print('recognized?')
            # Remove C(=O)O pattern regardless of position
            cleaned = re.sub(r'\(C\(=O\)O\)', '', content)
            # Remove any leftover empty parentheses
            cleaned = re.sub(r'\(\)', '', cleaned)
            print(cleaned)
            return cleaned
        return content
    
    def identify_residue(self, segment):
        """Identify residue with Pro reconstruction"""
        # Only clean terminal carboxyl if this is the last segment
        content = self.clean_terminal_carboxyl(segment)
        mods = self.get_modifications(segment)
        
        # Proline (P) - flexible ring numbers
        if any([
            # Check for any ring number in bond patterns
            (segment.get('bond_after', '').startswith(f'N{n}C(=O)') and 'CCC' in content and 
            any(f'[C@@H]{n}' in content or f'[C@H]{n}' in content for n in '123456789'))
            for n in '123456789'
        ]) or any([(segment.get('bond_before', '').startswith(f'C(=O)N{n}') and 'CCC' in content and 
            any(f'CCC{n}' for n in '123456789'))
            for n in '123456789'
        ]) or any([
            # Check ending patterns with any ring number
            (f'CCCN{n}' in content and content.endswith('=O') and 
            any(f'[C@@H]{n}' in content or f'[C@H]{n}' in content for n in '123456789'))
            for n in '123456789'
        ]) or any([
            # Handle CCC[C@H]n patterns
            (content == f'CCC[C@H]{n}' and segment.get('bond_before', '').startswith(f'C(=O)N{n}')) or
            (content == f'CCC[C@@H]{n}' and segment.get('bond_before', '').startswith(f'C(=O)N{n}')) or
            # N-terminal Pro with any ring number
            (f'N{n}CCC[C@H]{n}' in content) or
            (f'N{n}CCC[C@@H]{n}' in content)
            for n in '123456789'
        ]):
            return 'Pro', mods

        # Tryptophan (W) - more specific indole pattern
        if re.search(r'c[0-9]c\[nH\]c[0-9]ccccc[0-9][0-9]', content) and \
        'c[nH]c' in content.replace(' ', ''):
            return 'Trp', mods
        
        # Lysine (K)
        if '[C@@H](CCCCN)' in content or '[C@H](CCCCN)' in content:
            return 'Lys', mods
            
        # Arginine (R)
        if '[C@@H](CCCNC(=N)N)' in content or '[C@H](CCCNC(=N)N)' in content:
            return 'Arg', mods
        
        if ('NCC(=O)' in content) or (content == 'C'):
            if segment.get('bond_before') and segment.get('bond_after'):
                if ('C(=O)N' in segment['bond_before'] or 'C(=O)N(C)' in segment['bond_before']):
                    return 'Gly', mods
            elif segment.get('bond_before') and segment.get('bond_before').startswith('C(=O)N'):
                return 'Gly', mods
            
        if 'CC(C)C[C@H]' in content or 'CC(C)C[C@@H]' in content or '[C@@H](CC(C)C)' in content or '[C@H](CC(C)C)' in content or (('N[C@H](CCC(C)C)' in content or 'N[C@@H](CCC(C)C)' in content) and segment.get('bond_before') is None):
            return 'Leu', mods

        if '[C@@H]([C@@H](C)O)' in content or '[C@H]([C@H](C)O)' in content:
            return 'Thr', mods
        if re.search(r'\[C@H\]\(Cc\d+ccccc\d+\)', content) or re.search(r'\[C@@H\]\(Cc\d+ccccc\d+\)', content):
            return 'Phe', mods

        if ('[C@H](C(C)C)' in content or 
            '[C@@H](C(C)C)' in content or    
            '[C@H]C(C)C' in content or     
            '[C@@H]C(C)C' in content
            ): 
            if not any(p in content for p in ['CC(C)C[C@H]', 'CC(C)C[C@@H]']):  # Still check not Leu
                return 'Val', mods
            
        if any([
            'CC[C@H](C)' in content,
            'CC[C@@H](C)' in content,
            '[C@@H](CC)C' in content,
            '[C@H](CC)C' in content,
            'C(C)C[C@H]' in content and 'CC(C)C' not in content,
            'C(C)C[C@@H]' in content and 'CC(C)C' not in content
        ]):
            return 'Ile', mods
        
        if ('[C@H](C)' in content or '[C@@H](C)' in content):
            if not any(p in content for p in ['C(C)C', 'COC', 'CN(', 'C(C)O', 'CC[C@H]', 'CC[C@@H]']):
                return 'Ala', mods
        
        # Tyrosine (Tyr) - 4-hydroxybenzyl side chain
        if re.search(r'Cc[0-9]ccc\(O\)cc[0-9]', content):
            return 'Tyr', mods

        # Serine (Ser) - Hydroxymethyl side chain
        if '[C@H](CO)' in content or '[C@@H](CO)' in content:
            if not ('C(C)O' in content or 'COC' in content):
                return 'Ser', mods
        
        # Threonine (Thr) - 1-hydroxyethyl side chain
        if '[C@@H]([C@@H](C)O)' in content or '[C@H]([C@H](C)O)' in content or '[C@@H](C)O' in content or '[C@H](C)O' in content:
            return 'Thr', mods
        
        # Cysteine (Cys) - Thiol side chain
        if '[C@H](CS)' in content or '[C@@H](CS)' in content:
            return 'Cys', mods
        
        # Methionine (Met) - Methylthioethyl side chain
        if ('CCSC' in content):
            return 'Met', mods
                
        # Glutamine (Gln) - Carbamoylethyl side chain
        if (content == '[C@@H](CC' or content == '[C@H](CC' and segment.get('bond_before')=='C(=O)N' and segment.get('bond_after')=='C(=O)N') or ('CCC(=O)N' in content) or ('CCC(N)=O' in content):
            return 'Gln', mods
        # Asparagine (Asn) - Carbamoylmethyl side chain
        if (content == '[C@@H](C' or content == '[C@H](C' and segment.get('bond_before')=='C(=O)N' and segment.get('bond_after')=='C(=O)N') or ('CC(=O)N' in content) or ('CCN(=O)' in content) or ('CC(N)=O' in content):
            return 'Asn', mods

        # Glutamic acid (Glu) - Carboxyethyl side chain
        if ('CCC(=O)O' in content):
            return 'Glu', mods        
        # Aspartic acid (Asp) - Carboxymethyl side chain
        if ('CC(=O)O' in content):
            return 'Asp', mods
        
        # Arginine (Arg) - 3-guanidinopropyl side chain
        if ('CCCNC(=N)N' in content):
            return 'Arg', mods
        
        # Histidine (His) - Imidazole side chain
        if re.search(r'Cc\d+c\[nH\]cn\d+', content) or re.search(r'Cc\d+cnc\[nH\]\d+', content):
            return 'His', mods
        
        ############UAA
        
        if '[C@H](COC(C)(C)C)' in content or '[C@@H](COC(C)(C)C)' in content:
            return 'O-tBu', mods
        
        if re.search(r'c\d+ccccc\d+', content):
            if '[C@@H](c1ccccc1)' in content or '[C@H](c1ccccc1)' in content:
                return '4', mods  # Base phenylglycine
        if ('C[C@H](CCCC)' in content or 'C[C@@H](CCCC)' in content) and 'CC(C)' not in content:
            return 'Nle', mods
            
        # Ornithine (Orn) - 3-carbon chain with NH2
        if ('C[C@H](CCCN)' in content or 'C[C@@H](CCCN)' in content) and 'CC(C)' not in content:
            return 'Orn', mods
            
        # 2-Naphthylalanine (2Nal)
        if ('Cc3cc2ccccc2c3' in content):
            return '2Nal', mods
            
        # Cyclohexylalanine (Cha)
        if 'N2CCCCC2' in content or 'CCCCC2' in content:
            return 'Cha', mods
            
        # Aminobutyric acid (Abu) - 2-carbon chain
        if ('C[C@H](CC)' in content or 'C[C@@H](CC)' in content) and not any(p in content for p in ['CC(C)', 'CCCC', 'CCC(C)']):
            return 'Abu', mods
            
        # Pipecolic acid (Pip)
        if ('N3CCCCC3' in content or 'CCCCC3' in content):
            return 'Pip', mods

        # Cyclohexylglycine (Chg) - direct cyclohexyl without CH2
        if ('C[C@H](C1CCCCC1)' in content or 'C[C@@H](C1CCCCC1)' in content):
            return 'Chg', mods
            
        # 4-Fluorophenylalanine (4F-Phe)
        if ('Cc2ccc(F)cc2' in content):
            return '4F-Phe', mods
                
        # 4-substituted phenylalanines
        if 'Cc1ccc' in content:
            if 'OMe' in content or 'OCc1ccc' in content:
                return '0A1', mods  # 4-methoxy-Phenylalanine
            elif 'Clc1ccc' in content:
                return '200', mods  # 4-chloro-Phenylalanine
            elif 'Brc1ccc' in content:
                return '4BF', mods  # 4-Bromo-phenylalanine
            elif 'C#Nc1ccc' in content:
                return '4CF', mods  # 4-cyano-phenylalanine
            elif 'Ic1ccc' in content:
                return 'PHI', mods  # 4-Iodo-phenylalanine
            elif 'Fc1ccc' in content:
                return 'PFF', mods  # 4-Fluoro-phenylalanine
                
        # Modified tryptophans
        if 'c[nH]c2' in content:
            if 'Oc2cccc2' in content:
                return '0AF', mods  # 7-hydroxy-tryptophan
            elif 'Fc2cccc2' in content:
                return '4FW', mods  # 4-fluoro-tryptophan
            elif 'Clc2cccc2' in content:
                return '6CW', mods  # 6-chloro-tryptophan
            elif 'Brc2cccc2' in content:
                return 'BTR', mods  # 6-bromo-tryptophan
            elif 'COc2cccc2' in content:
                return 'MOT5', mods  # 5-Methoxy-tryptophan
            elif 'Cc2cccc2' in content:
                return 'MTR5', mods  # 5-Methyl-tryptophan
                
        # Special amino acids
        if 'CC(C)(C)[C@@H]' in content or 'CC(C)(C)[C@H]' in content:
            return 'BUG', mods  # Tertleucine
            
        if 'CCCNC(=N)N' in content:
            return 'CIR', mods  # Citrulline
            
        if '[SeH]' in content:
            return 'CSE', mods  # Selenocysteine
            
        if '[NH3]CC[C@@H]' in content or '[NH3]CC[C@H]' in content:
            return 'DAB', mods  # Diaminobutyric acid
            
        if 'C1CCCCC1' in content:
            if 'C1CCCCC1[C@@H]' in content or 'C1CCCCC1[C@H]' in content:
                return 'CHG', mods  # Cyclohexylglycine
            elif 'C1CCCCC1C[C@@H]' in content or 'C1CCCCC1C[C@H]' in content:
                return 'ALC', mods  # 3-cyclohexyl-alanine
                
        # Naphthalene derivatives
        if 'c1cccc2c1cccc2' in content:
            if 'c1cccc2c1cccc2[C@@H]' in content or 'c1cccc2c1cccc2[C@H]' in content:
                return 'NAL', mods  # 2-Naphthyl-alanine
                
        # Heteroaromatic derivatives
        if 'c1cncc' in content:
            return 'PYR4', mods  # 3-(4-Pyridyl)-alanine
        if 'c1cscc' in content:
            return 'THA3', mods  # 3-(3-thienyl)-alanine
        if 'c1nnc' in content:
            return 'TRZ4', mods  # 3-(1,2,4-Triazol-1-yl)-alanine
            
        # Modified serines and threonines
        if 'OP(O)(O)O' in content:
            if '[C@@H](COP' in content or '[C@H](COP' in content:
                return 'SEP', mods  # phosphoserine
            elif '[C@@H](OP' in content or '[C@H](OP' in content:
                return 'TPO', mods  # phosphothreonine
            
        # Specialized ring systems
        if 'c1c2ccccc2cc2c1cccc2' in content:
            return 'ANTH', mods  # 3-(9-anthryl)-alanine
        if 'c1csc2c1cccc2' in content:
            return 'BTH3', mods  # 3-(3-benzothienyl)-alanine
        if '[C@]12C[C@H]3C[C@@H](C2)C[C@@H](C1)C3' in content:
            return 'ADAM', mods  # Adamanthane

        # Fluorinated derivatives
        if 'FC(F)(F)' in content:
            if 'CC(F)(F)F' in content:
                return 'FLA', mods  # Trifluoro-alanine
            if 'C(F)(F)F)c1' in content:
                if 'c1ccccc1C(F)(F)F' in content:
                    return 'TFG2', mods  # 2-(Trifluoromethyl)-phenylglycine
                if 'c1cccc(c1)C(F)(F)F' in content:
                    return 'TFG3', mods  # 3-(Trifluoromethyl)-phenylglycine
                if 'c1ccc(cc1)C(F)(F)F' in content:
                    return 'TFG4', mods  # 4-(Trifluoromethyl)-phenylglycine
        
        # Multiple halogen patterns
        if 'F' in content and 'c1' in content:
            if 'c1ccc(c(c1)F)F' in content:
                return 'F2F', mods  # 3,4-Difluoro-phenylalanine
            if 'cc(F)cc(c1)F' in content:
                return 'WFP', mods  # 3,5-Difluoro-phenylalanine
        if 'Cl' in content and 'c1' in content:
            if 'c1ccc(cc1Cl)Cl' in content:
                return 'CP24', mods  # 2,4-dichloro-phenylalanine
            if 'c1ccc(c(c1)Cl)Cl' in content:
                return 'CP34', mods  # 3,4-dichloro-phenylalanine

        # Hydroxy and amino derivatives
        if 'O' in content and 'c1' in content:
            if 'c1cc(O)cc(c1)O' in content:
                return '3FG', mods  # (2s)-amino(3,5-dihydroxyphenyl)-ethanoic acid
            if 'c1ccc(c(c1)O)O' in content:
                return 'DAH', mods  # 3,4-Dihydroxy-phenylalanine
        
        # Modified histidines
        if 'c1cnc' in content:
            if '[C@@H]1CN[C@@H](N1)F' in content:
                return '2HF', mods  # 2-fluoro-l-histidine
            if 'c1cnc([nH]1)F' in content:
                return '2HF1', mods  # 2-fluoro-l-histidine variant
            if 'c1c[nH]c(n1)F' in content:
                return '2HF2', mods  # 2-fluoro-l-histidine variant

        if '[SeH]' in content:
            return 'CSE', mods  # Selenocysteine
        if 'S' in content:
            if 'CSCc1ccccc1' in content:
                return 'BCS', mods  # benzylcysteine
            if 'CCSC' in content:
                return 'ESC', mods  # Ethionine
            if 'CCS' in content:
                return 'HCS', mods  # homocysteine

        if 'CN=[N]=N' in content:
            return 'AZDA', mods  # azido-alanine
        if '[NH]=[C](=[NH2])=[NH2]' in content:
            if 'CCC[NH]=' in content:
                return 'AGM', mods  # 5-methyl-arginine
            if 'CC[NH]=' in content:
                return 'GDPR', mods  # 2-Amino-3-guanidinopropionic acid
        
        # Others    
        if 'C1CCCC1' in content:
            return 'CPA3', mods  # 3-Cyclopentyl-alanine
        if 'C1CCCCC1' in content:
            if 'CC1CCCCC1' in content:
                return 'ALC', mods  # 3-cyclohexyl-alanine
            else:
                return 'CHG', mods  # Cyclohexylglycine

        if 'CCC[C@@H]' in content or 'CCC[C@H]' in content:
            return 'NLE', mods  # Norleucine
        if 'CC[C@@H]' in content or 'CC[C@H]' in content:
            if not any(x in content for x in ['CC(C)', 'COC', 'CN(']):
                return 'ABA', mods  # 2-Aminobutyric acid
        if 'CCON' in content:
            return 'CAN', mods  # canaline
        if '[C@@H]1C=C[C@@H](C=C1)' in content:
            return 'ACZ', mods  # cis-amiclenomycin
        if 'CCC(=O)[NH3]' in content:
            return 'ONL', mods  # 5-oxo-l-norleucine
        if 'c1ccncc1' in content:
            return 'PYR4', mods  # 3-(4-Pyridyl)-alanine
        if 'c1ccco1' in content:
            return 'FUA2', mods  # (2-furyl)-alanine
            
        if 'c1ccc' in content:
            if 'c1ccc(cc1)c1ccccc1' in content:
                return 'BIF', mods  # 4,4-biphenylalanine
            if 'c1ccc(cc1)C(=O)c1ccccc1' in content:
                return 'PBF', mods  # 4-benzoyl-phenylalanine
            if 'c1ccc(cc1)C(C)(C)C' in content:
                return 'TBP4', mods  # 4-tert-butyl-phenylalanine
            if 'c1ccc(cc1)[C](=[NH2])=[NH2]' in content:
                return '0BN', mods  # 4-carbamimidoyl-l-phenylalanine
            if 'c1cccc(c1)[C](=[NH2])=[NH2]' in content:
                return 'APM', mods  # m-amidinophenyl-3-alanine

        if 'O' in content:
            if '[C@H]([C@H](C)O)O' in content:
                return 'ILX', mods  # 4,5-dihydroxy-isoleucine
            if '[C@H]([C@@H](C)O)O' in content:
                return 'ALO', mods  # Allo-threonine
            if '[C@H](COP(O)(O)O)' in content:
                return 'SEP', mods  # phosphoserine
            if '[C@H]([C@@H](C)OP(O)(O)O)' in content:
                return 'TPO', mods  # phosphothreonine
            if '[C@H](c1ccc(O)cc1)O' in content:
                return 'OMX', mods  # (betar)-beta-hydroxy-l-tyrosine
            if '[C@H](c1ccc(c(Cl)c1)O)O' in content:
                return 'OMY', mods  # (betar)-3-chloro-beta-hydroxy-l-tyrosine

        if 'n1' in content:
            if 'n1cccn1' in content:
                return 'PYZ1', mods  # 3-(1-Pyrazolyl)-alanine
            if 'n1nncn1' in content:
                return 'TEZA', mods  # 3-(2-Tetrazolyl)-alanine
            if 'c2c(n1)cccc2' in content:
                return 'QU32', mods  # 3-(2-Quinolyl)-alanine
            if 'c1cnc2c(c1)cccc2' in content:
                return 'QU33', mods  # 3-(3-quinolyl)-alanine
            if 'c1ccnc2c1cccc2' in content:
                return 'QU34', mods  # 3-(4-quinolyl)-alanine
            if 'c1ccc2c(c1)nccc2' in content:
                return 'QU35', mods  # 3-(5-Quinolyl)-alanine
            if 'c1ccc2c(c1)cncc2' in content:
                return 'QU36', mods  # 3-(6-Quinolyl)-alanine
            if 'c1cnc2c(n1)cccc2' in content:
                return 'QX32', mods  # 3-(2-quinoxalyl)-alanine

        if 'N' in content:
            if '[NH3]CC[C@@H]' in content:
                return 'DAB', mods  # Diaminobutyric acid
            if '[NH3]C[C@@H]' in content:
                return 'DPP', mods  # 2,3-Diaminopropanoic acid
            if '[NH3]CCCCCC[C@@H]' in content:
                return 'HHK', mods  # (2s)-2,8-diaminooctanoic acid
            if 'CCC[NH]=[C](=[NH2])=[NH2]' in content:
                return 'GBUT', mods  # 2-Amino-4-guanidinobutryric acid
            if '[NH]=[C](=S)=[NH2]' in content:
                return 'THIC', mods  # Thio-citrulline

        if 'CC' in content:
            if 'CCCC[C@@H]' in content:
                return 'AHP', mods  # 2-Aminoheptanoic acid
            if 'CCC([C@@H])(C)C' in content:
                return 'I2M', mods  # 3-methyl-l-alloisoleucine
            if 'CC[C@H]([C@@H])C' in content:
                return 'IIL', mods  # Allo-Isoleucine
            if '[C@H](CCC(C)C)' in content:
                return 'HLEU', mods  # Homoleucine
            if '[C@@H]([C@@H](C)O)C' in content:
                return 'HLU', mods  # beta-hydroxyleucine

        if '[C@@H]' in content:
            if '[C@@H](C[C@@H](F))' in content:
                return 'FGA4', mods  # 4-Fluoro-glutamic acid
            if '[C@@H](C[C@@H](O))' in content:
                return '3GL', mods  # 4-hydroxy-glutamic-acid
            if '[C@@H](C[C@H](C))' in content:
                return 'LME', mods  # (3r)-3-methyl-l-glutamic acid
            if '[C@@H](CC[C@H](C))' in content:
                return 'MEG', mods  # (3s)-3-methyl-l-glutamic acid

        if 'S' in content:
            if 'SCC[C@@H]' in content:
                return 'HSER', mods  # homoserine
            if 'SCCN' in content:
                return 'SLZ', mods  # thialysine
            if 'SC(=O)' in content:
                return 'CSA', mods  # s-acetonylcysteine
            if '[S@@](=O)' in content:
                return 'SME', mods  # Methionine sulfoxide
            if 'S(=O)(=O)' in content:
                return 'OMT', mods  # Methionine sulfone

        if 'C=' in content:
            if 'C=C[C@@H]' in content:
                return '2AG', mods  # 2-Allyl-glycine
            if 'C=C[C@@H]' in content:
                return 'LVG', mods  # vinylglycine
            if 'C=Cc1ccccc1' in content:
                return 'STYA', mods  # Styrylalanine

        if '[C@@H]1Cc2c(C1)cccc2' in content:
            return 'IGL', mods  # alpha-amino-2-indanacetic acid
        if '[C](=[C](=O)=O)=O' in content:
            return '26P', mods  # 2-amino-6-oxopimelic acid
        if '[C](=[C](=O)=O)=C' in content:
            return '2NP', mods  # l-2-amino-6-methylene-pimelic acid
        if 'c1cccc2c1cc(O)cc2' in content:
            return 'NAO1', mods  # 5-hydroxy-1-naphthalene
        if 'c1ccc2c(c1)cc(O)cc2' in content:
            return 'NAO2', mods  # 6-hydroxy-2-naphthalene    
        return None, mods

    def get_modifications(self, segment):
        """Get modifications based on bond types"""
        mods = []
        if segment.get('bond_after'):
            if 'N(C)' in segment['bond_after'] or segment['bond_after'].startswith('C(=O)N(C)'):
                mods.append('N-Me')
            if 'OC(=O)' in segment['bond_after']:
                mods.append('O-linked')
        return mods

    def analyze_structure(self, smiles):
        """Main analysis function with debug output"""
        print("\nAnalyzing structure:", smiles)
        
        # Split into segments
        segments = self.split_on_bonds(smiles)
        
        print("\nSegment Analysis:")
        sequence = []
        for i, segment in enumerate(segments):
            print(f"\nSegment {i}:")
            print(f"Content: {segment['content']}")
            print(f"Bond before: {segment.get('bond_before', 'None')}")
            print(f"Bond after: {segment.get('bond_after', 'None')}")
            
            residue, mods = self.identify_residue(segment)
            if residue:
                if mods:
                    sequence.append(f"{residue}({','.join(mods)})")
                else:
                    sequence.append(residue)
                print(f"Identified as: {residue}")
                print(f"Modifications: {mods}")
            else:
                print(f"Warning: Could not identify residue in segment: {segment['content']}")
        
        # Check if cyclic
        is_cyclic, peptide_cycles, aromatic_cycles = self.is_cyclic(smiles)
        three_letter = '-'.join(sequence)
        one_letter = ''.join(self.three_to_one.get(aa.split('(')[0], 'X') for aa in sequence)
        
        if is_cyclic:
            three_letter = f"cyclo({three_letter})"
            one_letter = f"cyclo({one_letter})"
        
        print(f"\nFinal sequence: {three_letter}")
        print(f"One-letter code: {one_letter}")
        print(f"Is cyclic: {is_cyclic}")
        #print(f"Peptide cycles: {peptide_cycles}")
        #print(f"Aromatic cycles: {aromatic_cycles}")
        
        return {
            'three_letter': three_letter,
            'one_letter': one_letter,
            'is_cyclic': is_cyclic
        }
        
def annotate_cyclic_structure(mol, sequence):
    """Create structure visualization"""
    AllChem.Compute2DCoords(mol)
    
    drawer = Draw.rdMolDraw2D.MolDraw2DCairo(2000, 2000)
    
    # Draw molecule first
    drawer.drawOptions().addAtomIndices = False
    drawer.DrawMolecule(mol)
    drawer.FinishDrawing()
    
    # Convert to PIL Image
    img = Image.open(BytesIO(drawer.GetDrawingText()))
    draw = ImageDraw.Draw(img)
    try:
        small_font = ImageFont.truetype("/usr/share/fonts/truetype/dejavu/DejaVuSans.ttf", 60)
    except OSError:
        try:
            small_font = ImageFont.truetype("arial.ttf", 60)
        except OSError:
            print("Warning: TrueType fonts not available, using default font")
            small_font = ImageFont.load_default()
    
    # Header
    seq_text = f"Sequence: {sequence}"
    bbox = draw.textbbox((1000, 100), seq_text, font=small_font)
    padding = 10
    draw.rectangle([bbox[0]-padding, bbox[1]-padding, 
                   bbox[2]+padding, bbox[3]+padding], 
                  fill='white', outline='white')
    draw.text((1000, 100), seq_text, 
             font=small_font, fill='black', anchor="mm")
    
    return img

def create_enhanced_linear_viz(sequence, smiles):
    """"Linear visualization"""
    analyzer = PeptideAnalyzer()
    
    fig = plt.figure(figsize=(15, 10))
    gs = fig.add_gridspec(2, 1, height_ratios=[1, 2])
    ax_struct = fig.add_subplot(gs[0])
    ax_detail = fig.add_subplot(gs[1])
    
    if sequence.startswith('cyclo('):
        residues = sequence[6:-1].split('-')
    else:
        residues = sequence.split('-')
    
    segments = analyzer.split_on_bonds(smiles)
    
    print(f"Number of residues: {len(residues)}")
    print(f"Number of segments: {len(segments)}")
    
    ax_struct.set_xlim(0, 10)
    ax_struct.set_ylim(0, 2)
    
    num_residues = len(residues)
    spacing = 9.0 / (num_residues - 1) if num_residues > 1 else 9.0
    
    y_pos = 1.5
    for i in range(num_residues):
        x_pos = 0.5 + i * spacing
        
        rect = patches.Rectangle((x_pos-0.3, y_pos-0.2), 0.6, 0.4, 
                               facecolor='lightblue', edgecolor='black')
        ax_struct.add_patch(rect)
        
        if i < num_residues - 1:
            segment = segments[i] if i < len(segments) else None
            if segment:
                bond_type = 'ester' if 'O-linked' in segment.get('bond_after', '') else 'peptide'
                is_n_methylated = 'N-Me' in segment.get('bond_after', '')
                
                bond_color = 'red' if bond_type == 'ester' else 'black'
                linestyle = '--' if bond_type == 'ester' else '-'
                
                ax_struct.plot([x_pos+0.3, x_pos+spacing-0.3], [y_pos, y_pos], 
                             color=bond_color, linestyle=linestyle, linewidth=2)
                
                mid_x = x_pos + spacing/2
                bond_label = f"{bond_type}"
                if is_n_methylated:
                    bond_label += "\n(N-Me)"
                ax_struct.text(mid_x, y_pos+0.1, bond_label, 
                             ha='center', va='bottom', fontsize=10, 
                             color=bond_color)
        
        ax_struct.text(x_pos, y_pos-0.5, residues[i], 
                      ha='center', va='top', fontsize=14)
    
    ax_detail.set_ylim(0, len(segments)+1)
    ax_detail.set_xlim(0, 1)
    
    segment_y = len(segments)
    for i, segment in enumerate(segments):
        y = segment_y - i
        
        # Check if this is a bond or residue
        residue, mods = analyzer.identify_residue(segment)
        if residue:
            text = f"Residue {i+1}: {residue}"
            if mods:
                text += f" ({', '.join(mods)})"
            color = 'blue'
        else:
            # Must be a bond
            text = f"Bond {i}: "
            if 'O-linked' in segment.get('bond_after', ''):
                text += "ester"
            elif 'N-Me' in segment.get('bond_after', ''):
                text += "peptide (N-methylated)"
            else:
                text += "peptide"
            color = 'red'
        
        ax_detail.text(0.05, y, text, fontsize=12, color=color)
        ax_detail.text(0.5, y, f"SMILES: {segment.get('content', '')}", fontsize=10, color='gray')
    
    # If cyclic, add connection indicator
    if sequence.startswith('cyclo('):
        ax_struct.annotate('', xy=(9.5, y_pos), xytext=(0.5, y_pos),
                          arrowprops=dict(arrowstyle='<->', color='red', lw=2))
        ax_struct.text(5, y_pos+0.3, 'Cyclic Connection', 
                      ha='center', color='red', fontsize=14)
    
    ax_struct.set_title("Peptide Structure Overview", pad=20)
    ax_detail.set_title("Segment Analysis Breakdown", pad=20)
    
    for ax in [ax_struct, ax_detail]:
        ax.set_xticks([])
        ax.set_yticks([])
        ax.axis('off')
    
    plt.tight_layout()
    return fig

class PeptideStructureGenerator:
    """Generate 3D structures of peptides using different embedding methods"""
    
    @staticmethod
    def prepare_molecule(smiles):
        """Prepare molecule with proper hydrogen handling"""
        mol = Chem.MolFromSmiles(smiles, sanitize=False)
        if mol is None:
            raise ValueError("Failed to create molecule from SMILES")
        
        for atom in mol.GetAtoms():
            atom.UpdatePropertyCache(strict=False)
        
        # Sanitize with reduced requirements
        Chem.SanitizeMol(mol, 
                        sanitizeOps=Chem.SANITIZE_FINDRADICALS|
                                  Chem.SANITIZE_KEKULIZE|
                                  Chem.SANITIZE_SETAROMATICITY|
                                  Chem.SANITIZE_SETCONJUGATION|
                                  Chem.SANITIZE_SETHYBRIDIZATION|
                                  Chem.SANITIZE_CLEANUPCHIRALITY)
        
        mol = Chem.AddHs(mol)
        return mol

    @staticmethod
    def get_etkdg_params(attempt=0):
        """Get ETKDG parameters"""
        params = AllChem.ETKDGv3()
        params.randomSeed = -1
        params.maxIterations = 200
        params.numThreads = 4  # Reduced for web interface
        params.useBasicKnowledge = True
        params.enforceChirality = True
        params.useExpTorsionAnglePrefs = True
        params.useSmallRingTorsions = True
        params.useMacrocycleTorsions = True
        params.ETversion = 2
        params.pruneRmsThresh = -1
        params.embedRmsThresh = 0.5
        
        if attempt > 10:
            params.bondLength = 1.5 + (attempt - 10) * 0.02
            params.useExpTorsionAnglePrefs = False
        
        return params

    def generate_structure_etkdg(self, smiles, max_attempts=20):
        """Generate 3D structure using ETKDG without UFF optimization"""
        success = False
        mol = None
        
        for attempt in range(max_attempts):
            try:
                mol = self.prepare_molecule(smiles)
                params = self.get_etkdg_params(attempt)
                
                if AllChem.EmbedMolecule(mol, params) == 0:
                    success = True
                    break
            except Exception as e:
                continue
        
        if not success:
            raise ValueError("Failed to generate structure with ETKDG")
        
        return mol

    def generate_structure_uff(self, smiles, max_attempts=20):
        """Generate 3D structure using ETKDG followed by UFF optimization"""
        best_mol = None
        lowest_energy = float('inf')
        
        for attempt in range(max_attempts):
            try:
                test_mol = self.prepare_molecule(smiles)
                params = self.get_etkdg_params(attempt)
                
                if AllChem.EmbedMolecule(test_mol, params) == 0:
                    res = AllChem.UFFOptimizeMolecule(test_mol, maxIters=2000, 
                                                     vdwThresh=10.0, confId=0,
                                                     ignoreInterfragInteractions=True)
                    
                    if res == 0:
                        ff = AllChem.UFFGetMoleculeForceField(test_mol)
                        if ff:
                            current_energy = ff.CalcEnergy()
                            if current_energy < lowest_energy:
                                lowest_energy = current_energy
                                best_mol = Chem.Mol(test_mol)
            except Exception:
                continue
        
        if best_mol is None:
            raise ValueError("Failed to generate optimized structure")
        
        return best_mol

    @staticmethod
    def mol_to_sdf_bytes(mol):
        """Convert RDKit molecule to SDF file bytes"""
        sio = StringIO()
        writer = Chem.SDWriter(sio)
        writer.write(mol)
        writer.close()
        
        return sio.getvalue().encode('utf-8')

def process_input(smiles_input=None, file_obj=None, show_linear=False, 
                 show_segment_details=False, generate_3d=False, use_uff=False):
    """Process input and create visualizations using PeptideAnalyzer"""
    analyzer = PeptideAnalyzer()
    temp_dir = tempfile.mkdtemp() if generate_3d else None
    structure_files = []
    
    # Handle direct SMILES input
    if smiles_input:
        smiles = smiles_input.strip()
        
        if not analyzer.is_peptide(smiles):
            return "Error: Input SMILES does not appear to be a peptide structure.", None, None
                
        try:
            mol = Chem.MolFromSmiles(smiles)
            if mol is None:
                return "Error: Invalid SMILES notation.", None, None
            
            if generate_3d:
                generator = PeptideStructureGenerator()
                
                try:
                    # Generate ETKDG structure
                    mol_etkdg = generator.generate_structure_etkdg(smiles)
                    etkdg_path = os.path.join(temp_dir, "structure_etkdg.sdf")
                    writer = Chem.SDWriter(etkdg_path)
                    writer.write(mol_etkdg)
                    writer.close()
                    structure_files.append(etkdg_path)
                    
                    # Generate UFF structure if requested
                    if use_uff:
                        mol_uff = generator.generate_structure_uff(smiles)
                        uff_path = os.path.join(temp_dir, "structure_uff.sdf")
                        writer = Chem.SDWriter(uff_path)
                        writer.write(mol_uff)
                        writer.close()
                        structure_files.append(uff_path)
                
                except Exception as e:
                    return f"Error generating 3D structures: {str(e)}", None, None, None
                
            segments = analyzer.split_on_bonds(smiles)
            
            sequence_parts = []
            output_text = ""
            
            # Only include segment analysis in output if requested
            if show_segment_details:
                output_text += "Segment Analysis:\n"
                for i, segment in enumerate(segments):
                    output_text += f"\nSegment {i}:\n"
                    output_text += f"Content: {segment['content']}\n"
                    output_text += f"Bond before: {segment.get('bond_before', 'None')}\n"
                    output_text += f"Bond after: {segment.get('bond_after', 'None')}\n"
                    
                    residue, mods = analyzer.identify_residue(segment)
                    if residue:
                        if mods:
                            sequence_parts.append(f"{residue}({','.join(mods)})")
                        else:
                            sequence_parts.append(residue)
                        output_text += f"Identified as: {residue}\n"
                        output_text += f"Modifications: {mods}\n"
                    else:
                        output_text += f"Warning: Could not identify residue in segment: {segment['content']}\n"
                output_text += "\n"
            else:
                for segment in segments:
                    residue, mods = analyzer.identify_residue(segment)
                    if residue:
                        if mods:
                            sequence_parts.append(f"{residue}({','.join(mods)})")
                        else:
                            sequence_parts.append(residue)
            
            is_cyclic, peptide_cycles, aromatic_cycles = analyzer.is_cyclic(smiles)
            three_letter = '-'.join(sequence_parts)
            one_letter = ''.join(analyzer.three_to_one.get(aa.split('(')[0], 'X') for aa in sequence_parts)
        
            if is_cyclic:
                three_letter = f"cyclo({three_letter})"
                one_letter = f"cyclo({one_letter})"
            
            img_cyclic = annotate_cyclic_structure(mol, three_letter)
            
            # Create linear representation if requested
            img_linear = None
            if show_linear:
                fig_linear = create_enhanced_linear_viz(three_letter, smiles)
                buf = BytesIO()
                fig_linear.savefig(buf, format='png', bbox_inches='tight', dpi=300)
                buf.seek(0)
                img_linear = Image.open(buf)
                plt.close(fig_linear)

            summary = "Summary:\n"
            summary += f"Sequence: {three_letter}\n"
            summary += f"One-letter code: {one_letter}\n"
            summary += f"Is Cyclic: {'Yes' if is_cyclic else 'No'}\n"
            #if is_cyclic:
                #summary += f"Peptide Cycles: {', '.join(peptide_cycles)}\n"
                #summary += f"Aromatic Cycles: {', '.join(aromatic_cycles)}\n"
            
            if structure_files:
                summary += "\n3D Structures Generated:\n"
                for filepath in structure_files:
                    summary += f"- {os.path.basename(filepath)}\n"
            
            return summary + output_text, img_cyclic, img_linear, structure_files if structure_files else None
            
        except Exception as e:
            return f"Error processing SMILES: {str(e)}", None, None, None
    
    # Handle file input
    if file_obj is not None:
        try:
            if hasattr(file_obj, 'name'):
                with open(file_obj.name, 'r') as f:
                    content = f.read()
            else:
                content = file_obj.decode('utf-8') if isinstance(file_obj, bytes) else str(file_obj)
            
            output_text = ""
            for line in content.splitlines():
                smiles = line.strip()
                if smiles:
                    if not analyzer.is_peptide(smiles):
                        output_text += f"Skipping non-peptide SMILES: {smiles}\n"
                        continue
                    
                    segments = analyzer.split_on_bonds(smiles)
                    sequence_parts = []
                    
                    if show_segment_details:
                        output_text += f"\nSegment Analysis for SMILES: {smiles}\n"
                        for i, segment in enumerate(segments):
                            output_text += f"\nSegment {i}:\n"
                            output_text += f"Content: {segment['content']}\n"
                            output_text += f"Bond before: {segment.get('bond_before', 'None')}\n"
                            output_text += f"Bond after: {segment.get('bond_after', 'None')}\n"
                            residue, mods = analyzer.identify_residue(segment)
                            if residue:
                                if mods:
                                    sequence_parts.append(f"{residue}({','.join(mods)})")
                                else:
                                    sequence_parts.append(residue)
                                output_text += f"Identified as: {residue}\n"
                                output_text += f"Modifications: {mods}\n"
                    else:
                        for segment in segments:
                            residue, mods = analyzer.identify_residue(segment)
                            if residue:
                                if mods:
                                    sequence_parts.append(f"{residue}({','.join(mods)})")
                                else:
                                    sequence_parts.append(residue)
                    
                    is_cyclic, peptide_cycles, aromatic_cycles = analyzer.is_cyclic(smiles)
                    sequence = f"cyclo({'-'.join(sequence_parts)})" if is_cyclic else '-'.join(sequence_parts)
                    
                    output_text += f"\nSummary for SMILES: {smiles}\n"
                    output_text += f"Sequence: {sequence}\n"
                    output_text += f"Is Cyclic: {'Yes' if is_cyclic else 'No'}\n"
                    if is_cyclic:
                        output_text += f"Peptide Cycles: {', '.join(peptide_cycles)}\n"
                    output_text += "-" * 50 + "\n"
            
            return output_text, None, None
            
        except Exception as e:
            return f"Error processing file: {str(e)}", None, None
    
    return "No input provided.", None, None

iface = gr.Interface(
    fn=process_input,
    inputs=[
        gr.Textbox(
            label="Enter SMILES string",
            placeholder="Enter SMILES notation of peptide...",
            lines=2
        ),
        gr.File(
            label="Or upload a text file with SMILES",
            file_types=[".txt"]
        ),
        gr.Checkbox(
            label="Show linear representation",
            value=False
        ),
        gr.Checkbox(
            label="Show segment details",
            value=False
        ),
        gr.Checkbox(
            label="Generate 3D structure (sdf file format)",
            value=False
        ),
        gr.Checkbox(
            label="Use UFF optimization (may take long)",
            value=False
        )
    ],
    outputs=[
        gr.Textbox(
            label="Analysis Results",
            lines=10
        ),
        gr.Image(
            label="2D Structure with Annotations",
            type="pil"
        ),
        gr.Image(
            label="Linear Representation",
            type="pil"
        ),
        gr.File(
            label="3D Structure Files",
            file_count="multiple"
        )
    ],
    title="Peptide Structure Analyzer and Visualizer",
    description="""
    Analyze and visualize peptide structures from SMILES notation:
    1. Validates if the input is a peptide structure
    2. Determines if the peptide is cyclic
    3. Parses the amino acid sequence
    4. Creates 2D structure visualization with residue annotations
    5. Optional linear representation
    6. Optional 3D structure generation (ETKDG and UFF methods)
    
    Input: Either enter a SMILES string directly or upload a text file containing SMILES strings
    
    Example SMILES strings (copy and paste):
    ```
    CC(C)C[C@@H]1NC(=O)[C@@H](CC(C)C)N(C)C(=O)[C@@H](C)N(C)C(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H]2CCCN2C1=O
    ```
    ```
    C(C)C[C@@H]1NC(=O)[C@@H]2CCCN2C(=O)[C@@H](CC(C)C)NC(=O)[C@@H](CC(C)C)N(C)C(=O)[C@H](C)NC(=O)[C@H](Cc2ccccc2)NC1=O
    ```
    ```
    CC(C)C[C@H]1C(=O)N(C)[C@@H](Cc2ccccc2)C(=O)NCC(=O)N[C@H](C(=O)N2CCCCC2)CC(=O)N(C)CC(=O)N[C@@H]([C@@H](C)O)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N(C)[C@@H](Cc2ccccc2)C(=O)N1C
    ```
    """,
    flagging_mode="never"
)

if __name__ == "__main__":
    iface.launch(share=True)