app.py

import os
import gradio as gr
import gradio.blocks
from gradio.blocks import Blocks

original_get_api_info = Blocks.get_api_info

def safe_get_api_info(self):
    try:
        return original_get_api_info(self)
    except Exception as e:
        print("⚠️ Failed to generate API schema:", e)
        return {}

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
        ]
        self.complex_residue_patterns = [
            # Kpg - Lys(palmitoyl-Glu-OtBu)
            (r'\[C[@]H\]\(CCCNC\(=O\)CCC\[C@@H\]\(NC\(=O\)CCCCCCCCCCCCCCCC\)C\(=O\)OC\(C\)\(C\)C\)', 'Kpg'),
            (r'CCCCCCCCCCCCCCCCC\(=O\)N\[C@H\]\(CCCC\(=O\)NCCC\[C@@H\]', 'Kpg'),
            (r'\[C[@]?H\]\(CSC\(c\d+ccccc\d+\)\(c\d+ccccc\d+\)c\d+ccc\(OC\)cc\d+\)', 'Cmt'),
            (r'CSC\(c.*?c.*?OC\)', 'Cmt'),        # Core structure of Cys-Mmt group
            (r'COc.*?ccc\(C\(SC', 'Cmt'),         # Start of Cmt in cyclic peptides
            (r'c2ccccc2\)c2ccccc2\)cc', 'Cmt'),   # End of Cmt in cyclic peptides
            # Glu(OAll)
            (r'C=CCOC\(=O\)CC\[C@@H\]', 'Eal'),
            #(r'COc\d+ccc\(C\(SC\[C@@H\]\d+.*?\)\(c\d+ccccc\d+\)c\d+ccccc\d+\)cc\d+', 'Cmt-cyclic'),

            # Dtg - Asp(OtBu)-(Dmb)Gly
            (r'CN\(Cc\d+ccc\(OC\)cc\d+OC\)C\(=O\)\[C@H\]\(CC\(=O\)OC\(C\)\(C\)C\)', 'Dtg'),
            (r'C\(=O\)N\(CC\d+=C\(C=C\(C=C\d+\)OC\)OC\)CC\(=O\)', 'Dtg'),
            (r'N\[C@@H\]\(CC\(=O\)OC\(C\)\(C\)C\)C\(=O\)N\(CC\d+=C\(C=C\(C=C\d+\)OC\)OC\)CC\(=O\)', 'Dtg'),
        ]
        # 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',
            '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', 'Cmt-cyclic': 'Ĉ',
            'Aib': 'Ŷ', 'Dtg': 'Ĝ', 'Cmt': 'Ĉ', 'Eal': 'Ė', 'Nml': "Ŀ", 'Nma': 'Ṃ',
            'Kpg': 'Ƙ', 'Tpb': 'Ṯ', 'Cyl': 'Ċ', 'Nle': 'Ł', 'Hph': 'Ĥ', 'Cys-Cys': 'CC', 'cys-cys': 'cc',
        }

    def preprocess_complex_residues(self, smiles):
        complex_positions = []
        
        for pattern, residue_type in self.complex_residue_patterns:
            for match in re.finditer(pattern, smiles):
                # Only add if this position doesn't overlap with existing matches
                if not any(pos['start'] <= match.start() < pos['end'] or 
                          pos['start'] < match.end() <= pos['end'] for pos in complex_positions):
                    complex_positions.append({
                        'start': match.start(),
                        'end': match.end(),
                        'type': residue_type,
                        'pattern': match.group()
                    })
        
        # Sort by position (to handle potential overlapping matches)
        complex_positions.sort(key=lambda x: x['start'])
        
        if not complex_positions:
            return smiles, []
        
        # Build a new SMILES string, protecting complex residues
        preprocessed_smiles = smiles
        offset = 0  # Track offset from replacements
        
        protected_residues = []
        
        for pos in complex_positions:
            start = pos['start'] + offset
            end = pos['end'] + offset
            
            complex_part = preprocessed_smiles[start:end]
            
            if not ('[C@H]' in complex_part or '[C@@H]' in complex_part):
                continue
                
            placeholder = f"COMPLEX_RESIDUE_{len(protected_residues)}"
            
            preprocessed_smiles = preprocessed_smiles[:start] + placeholder + preprocessed_smiles[end:]
            
            offset += len(placeholder) - (end - start)
            
            protected_residues.append({
                'placeholder': placeholder,
                'type': pos['type'],
                'content': complex_part
            })
    
            #print(f"Protected {pos['type']}: {complex_part[:20]}... as {placeholder}")
        
        return preprocessed_smiles, protected_residues

    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, protected_residues=None):
        """Split SMILES into segments based on peptide bonds, with improved handling of protected residues"""
        positions = []
        used = set()
        
        # First, handle protected complex residues if any
        if protected_residues:
            for residue in protected_residues:
                match = re.search(residue['placeholder'], smiles)
                if match:
                    positions.append({
                        'start': match.start(),
                        'end': match.end(),
                        'type': 'complex',
                        'pattern': residue['placeholder'],
                        'residue_type': residue['type'],
                        'content': residue['content']
                    })
                    used.update(range(match.start(), match.end()))
        
        # Find all peptide bonds
        bond_positions = []
        
        # 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):
                bond_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):
                    bond_positions.append({
                        'start': match.start(),
                        'end': match.end(),
                        'type': bond_type,
                        'pattern': match.group()
                    })
                    used.update(range(match.start(), match.end()))
        
        bond_positions.sort(key=lambda x: x['start'])
        
        # Combine complex residue positions and bond positions
        all_positions = positions + bond_positions
        all_positions.sort(key=lambda x: x['start'])
        
        # Create segments
        segments = []
        
        if all_positions and all_positions[0]['start'] > 0:
            segments.append({
                'content': smiles[0:all_positions[0]['start']],
                'bond_after': all_positions[0]['pattern'] if all_positions[0]['type'] != 'complex' else None,
                'complex_after': all_positions[0]['pattern'] if all_positions[0]['type'] == 'complex' else None
            })
        
        for i in range(len(all_positions)-1):
            current = all_positions[i]
            next_pos = all_positions[i+1]
            
            if current['type'] == 'complex':
                segments.append({
                    'content': current['content'],
                    'bond_before': all_positions[i-1]['pattern'] if i > 0 and all_positions[i-1]['type'] != 'complex' else None,
                    'bond_after': next_pos['pattern'] if next_pos['type'] != 'complex' else None,
                    'complex_type': current['residue_type']
                })
            elif current['type'] == 'gly':
                segments.append({
                    'content': 'NCC(=O)',
                    'bond_before': all_positions[i-1]['pattern'] if i > 0 and all_positions[i-1]['type'] != 'complex' else None,
                    'bond_after': next_pos['pattern'] if next_pos['type'] != 'complex' else None
                })
            else:
                # Only create segment if there's content between this bond and next position
                content = smiles[current['end']:next_pos['start']]
                if content and next_pos['type'] != 'complex':
                    segments.append({
                        'content': content,
                        'bond_before': current['pattern'],
                        'bond_after': next_pos['pattern'] if next_pos['type'] != 'complex' else None
                    })
        
        if all_positions and all_positions[-1]['end'] < len(smiles):
            if all_positions[-1]['type'] == 'complex':
                segments.append({
                    'content': all_positions[-1]['content'],
                    'bond_before': all_positions[-2]['pattern'] if len(all_positions) > 1 and all_positions[-2]['type'] != 'complex' else None,
                    'complex_type': all_positions[-1]['residue_type']
                })
            else:
                segments.append({
                    'content': smiles[all_positions[-1]['end']:],
                    'bond_before': all_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
        if 'complex_type' in segment:
            return segment['complex_type'], []
        content = self.clean_terminal_carboxyl(segment)
        mods = self.get_modifications(segment)
        
        if content.startswith('COc1ccc(C(SC[C@@H]'):
            print("DIRECT MATCH: Found Cmt at beginning")
            return 'Cmt', mods

        if '[C@@H]3CCCN3C2=O)(c2ccccc2)c2ccccc2)cc' in content:
            print("DIRECT MATCH: Found Pro at end")
            return 'Pro', mods

        # Eal - Glu(OAll)
        if 'CCC(=O)OCC=C' in content or 'CC(=O)OCC=C' in content or 'C=CCOC(=O)CC' in content:
            return 'Eal', mods

        # 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

        # D-Proline (p)
        if ('N1[C@H](CCC1)' in content):
            return 'pro', mods

        # Tryptophan (W)
        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(' ', ''):
            if '[C@H](CC' in content:  # D-form
                return 'trp', mods
            return 'Trp', mods
        
        # Lysine (K) - both patterns
        if '[C@@H](CCCCN)' in content or '[C@H](CCCCN)' in content:
            if '[C@H](CCCCN)' in content:  # D-form
                return 'lys', mods
            return 'Lys', mods
                
        # Arginine (R) - both patterns
        if '[C@@H](CCCNC(=N)N)' in content or '[C@H](CCCNC(=N)N)' in content:
            if '[C@H](CCCNC(=N)N)' in content:  # D-form
                return 'arg', mods
            return 'Arg', mods
        
        if content == 'C' and segment.get('bond_before') and segment.get('bond_after'):
            # If it's surrounded by peptide bonds, it's almost certainly Gly
            if ('C(=O)N' in segment['bond_before'] or 'NC(=O)' in segment['bond_before'] or 'N(C)C(=O)' in segment['bond_before']) and \
               ('NC(=O)' in segment['bond_after'] or 'C(=O)N' in segment['bond_after'] or 'N(C)C(=O)' in segment['bond_after']):
                return 'Gly', mods
                
        # Leucine patterns (L/l)
        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):
            if '[C@H](CC(C)C)' in content or 'CC(C)C[C@H]' in content:  # D-form
                return 'leu', mods
            return 'Leu', mods

        # Threonine patterns (T/t)
        if '[C@@H]([C@@H](C)O)' in content or '[C@H]([C@H](C)O)' in content or '[C@@H]([C@H](C)O)' in content or '[C@H]([C@@H](C)O)' in content:
            # Check both stereochemistry patterns
            if '[C@H]([C@@H](C)O)' in content:  # D-form
                return 'thr', mods
            return 'Thr', mods
        
        if re.search(r'\[C@H\]\(CCc\d+ccccc\d+\)', content) or re.search(r'\[C@@H\]\(CCc\d+ccccc\d+\)', content):
            return 'Hph', mods    
        
        # Phenylalanine patterns (F/f)
        if re.search(r'\[C@H\]\(Cc\d+ccccc\d+\)', content) or re.search(r'\[C@@H\]\(Cc\d+ccccc\d+\)', content):
            if re.search(r'\[C@H\]\(Cc\d+ccccc\d+\)', content):  # D-form
                return 'phe', mods
            return 'Phe', mods

        if ('CC(C)[C@@H]' in content or 'CC(C)[C@H]' in content or 
            '[C@H](C(C)C)' in content or '[C@@H](C(C)C)' in content or
            'C(C)C[C@H]' in content or 'C(C)C[C@@H]' in content):
            
            # Make sure it's not leucine
            if not any(p in content for p in ['CC(C)C[C@H]', 'CC(C)C[C@@H]', 'CCC(=O)']):
                if '[C@H]' in content and not '[C@@H]' in content:  # D-form
                    return 'val', mods
                return 'Val', mods
                    
        # Isoleucine patterns (I/i)
        if any([
            'CC[C@@H](C)' in content, '[C@@H](C)CC' in content,
            '[C@@H](CC)C' in content,
            'C(C)C[C@@H]' in content and 'CC(C)C' not in content
        ]):
            if '[C@H]([C@@H](CC)C)' in content or '[C@H](CC)C' in content:  # D-form
                return 'ile', mods
            elif '[C@H](C)CC' in content or '[C@H](CC)C' in content or 'CC[C@H](C)' in content:
                return 'ile', mods
            elif 'C(C)C[C@H]' in content and 'CC(C)C' not in content:
                return 'ile', mods
            return 'Ile', mods
        
        # Alanine patterns (A/a)
        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]']):
                if '[C@H](C)' in content:  # D-form
                    return 'ala', mods
                return 'Ala', mods
        
        # Tyrosine patterns (Y/y)
        if re.search(r'Cc[0-9]ccc\(O\)cc[0-9]', content):
            if '[C@H](Cc1ccc(O)cc1)' in content:  # D-form
                return 'tyr', mods
            return 'Tyr', mods

        # Serine patterns (S/s)
        if '[C@H](CO)' in content or '[C@@H](CO)' in content:
            if not ('C(C)O' in content or 'COC' in content):
                if '[C@H](CO)' in content:  # D-form
                    return 'ser', mods
                return 'Ser', mods
            
        if 'CSSC' in content:
            if re.search(r'\[C@@H\].*CSSC.*\[C@@H\]', content) or re.search(r'\[C@H\].*CSSC.*\[C@H\]', content):
                if '[C@H]' in content and not '[C@@H]' in content:  # D-form
                    return 'cys-cys', mods
                return 'Cys-Cys', mods
                
            if '[C@@H](N)CSSC' in content or '[C@H](N)CSSC' in content:
                if '[C@H](N)CSSC' in content:  # D-form
                    return 'cys-cys', mods
                return 'Cys-Cys', mods
                
            if 'CSSC[C@@H](C(=O)O)' in content or 'CSSC[C@H](C(=O)O)' in content:
                if 'CSSC[C@H](C(=O)O)' in content:  # D-form
                    return 'cys-cys', mods
                return 'Cys-Cys', mods
            
        # Cysteine patterns (C/c)
        if '[C@H](CS)' in content or '[C@@H](CS)' in content:
            if '[C@H](CS)' in content:  # D-form
                return 'cys', mods
            return 'Cys', mods
        
        # Methionine patterns (M/m)
        if ('CCSC' in content) or ("CSCC" in content):
            if '[C@H](CCSC)' in content:  # D-form
                return 'met', mods
            elif '[C@H]' in content:
                return 'met', mods
            return 'Met', mods
                    
        # Glutamine patterns (Q/q)
        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):
            if '[C@H](CCC(=O)N)' in content:  # D-form
                return 'gln', mods
            return 'Gln', mods
            
        # Asparagine patterns (N/n)
        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):
            if '[C@H](CC(=O)N)' in content:  # D-form
                return 'asn', mods
            return 'Asn', mods

        # Glutamic acid patterns (E/e)
        if ('CCC(=O)O' in content):
            if '[C@H](CCC(=O)O)' in content:  # D-form
                return 'glu', mods
            return 'Glu', mods
            
        # Aspartic acid patterns (D/d)
        if ('CC(=O)O' in content):
            if '[C@H](CC(=O)O)' in content:  # D-form
                return 'asp', mods
            return 'Asp', mods
        
        if re.search(r'Cc\d+c\[nH\]cn\d+', content) or re.search(r'Cc\d+cnc\[nH\]\d+', content):
            if '[C@H]' in content:  # D-form
                return 'his', mods
            return 'His', mods
        if 'C2(CCCC2)' in content or 'C1(CCCC1)' in content or re.search(r'C\d+\(CCCC\d+\)', content):
            return 'Cyl', mods
        
        if ('N[C@@H](CCCC)' in content or '[C@@H](CCCC)' in content or 'CCCC[C@@H]' in content or 
            'N[C@H](CCCC)' in content or '[C@H](CCCC)' in content) and 'CC(C)' not in content:
            return 'Nle', mods
        # Aib - alpha-aminoisobutyric acid (2-aminoisobutyric acid)
        if 'C(C)(C)(N)' in content or 'C(C)(C)' in content or 'C(C)(C)' in content and ('C(=O)N' in segment['bond_before'] or 'NC(=O)' in segment['bond_before'] or 'N(C)C(=O)' in segment['bond_before']) and \
               ('NC(=O)' in segment['bond_after'] or 'C(=O)N' in segment['bond_after'] or 'N(C)C(=O)' in segment['bond_after']):
            return 'Aib', mods
        
        # Dtg - Asp(OtBu)-(Dmb)Gly
        if 'CC(=O)OC(C)(C)C' in content and 'CC1=C(C=C(C=C1)OC)OC' in content:
            return 'Dtg', mods
    
        
        # Kpg - Lys(palmitoyl-Glu-OtBu)
        if 'CCCNC(=O)' in content and 'CCCCCCCCCCCC' in content:
            return 'Kpg', mods
        
        # Tpb - Thr(PO(OBzl)OH)
        if re.search(r'\[C[@]?H\]\(C\)OP\(=O\)\(O\)', content) or 'OP(=O)(O)OCC' in content:
            return 'Tpb', mods
        
        return None, mods

    def get_modifications(self, segment):
        """Get modifications based on bond types and segment content - fixed to avoid duplicates"""
        mods = []
        
        # Check for N-methylation in any form, but only add it once
        # Check both bonds and segment content for N-methylation patterns
        if ((segment.get('bond_after') and 
            ('N(C)' in segment['bond_after'] or segment['bond_after'].startswith('C(=O)N(C)'))) or
            ('N(C)C(=O)' in segment['content'] or 'N(C)C1=O' in segment['content']) or
            (segment['content'].endswith('N(C)C(=O)') or segment['content'].endswith('N(C)C1=O'))):
            mods.append('N-Me')
        
        # Check for O-linked modifications
        #if segment.get('bond_after') and 'OC(=O)' in segment['bond_after']:
            #mods.append('O-linked')
        
        return mods

    def analyze_structure(self, smiles):
        """Main analysis function with preprocessing for complex residues"""
        print("\nAnalyzing structure:", smiles)

        # Pre-process to identify complex residues first
        preprocessed_smiles, protected_residues = self.preprocess_complex_residues(smiles)
        
        if protected_residues:
            print(f"Identified {len(protected_residues)} complex residues during pre-processing")
            for i, residue in enumerate(protected_residues):
                print(f"Complex residue {i+1}: {residue['type']}")

        
        # Check if it's cyclic
        is_cyclic, peptide_cycles, aromatic_cycles = self.is_cyclic(smiles)
        
        segments = self.split_on_bonds(preprocessed_smiles, protected_residues)
        
        print("\nSegment Analysis:")
        sequence = []
        for i, segment in enumerate(segments):
            print(f"\nSegment {i}:")
            print(f"Content: {segment.get('content', 'None')}")
            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.get('content', 'None')}")
        
        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,
            'residues': sequence
        }
        
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, []
                
            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 []
            
        except Exception as e:
            return f"Error processing SMILES: {str(e)}", 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 not smiles:
                    continue
                
                if not analyzer.is_peptide(smiles):
                    output_text += f"Skipping non-peptide SMILES: {smiles}\n"
                    continue
                
                try:
                    # Process the structure
                    result = analyzer.analyze_structure(smiles)
                    
                    output_text += f"\nSummary for SMILES: {smiles}\n"
                    output_text += f"Sequence: {result['three_letter']}\n"
                    output_text += f"One-letter code: {result['one_letter']}\n"
                    output_text += f"Is Cyclic: {'Yes' if result['is_cyclic'] else 'No'}\n"
                    output_text += "-" * 50 + "\n"
                except Exception as e:
                    output_text += f"Error processing SMILES: {smiles} - {str(e)}\n"
                    output_text += "-" * 50 + "\n"
            
            return output_text, None, None, []
            
        except Exception as e:
            return f"Error processing file: {str(e)}", None, None, []
    
    return (
            output_text or "No analysis done.",
            img_cyclic if 'img_cyclic' in locals() else None,
            img_linear if 'img_linear' in locals() else None,
            structure_files if structure_files else []
        )

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 show segmentation 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__":
    Blocks.get_api_info = safe_get_api_info
    iface.launch(share=True)