Homology modeling fundamentals MCQs With Answer

Homology modeling fundamentals MCQs With Answer

This quiz set introduces M.Pharm students to core concepts of homology (comparative) modeling, an essential computational technique used to predict three-dimensional protein structures from sequence similarity. Questions cover template selection, sequence alignment strategies, model building algorithms (such as MODELLER), loop and side-chain modeling, refinement techniques, and validation metrics like RMSD and Ramachandran analysis. Emphasis is placed on practical considerations—when comparative modeling is appropriate, how to assess template quality, and common pitfalls such as alignment errors and poorly modeled loops. Use these MCQs to test understanding and prepare for applications of homology modeling in drug design and structural bioinformatics.

Q1. What is the fundamental assumption behind homology (comparative) modeling?

• Proteins with similar functions always have identical sequences
• Proteins with similar sequences adopt similar three-dimensional structures
• All proteins fold into the same overall fold regardless of sequence
• Structure determines sequence rather than sequence determining structure

Correct Answer: Proteins with similar sequences adopt similar three-dimensional structures

Q2. Which sequence identity range is typically referred to as the “twilight zone” where structural homology becomes uncertain?

• Greater than 50%
• 30% to 50%
• 20% to 30%
• Less than 10%

Correct Answer: 20% to 30%

Q3. What is the very first practical step in building a homology model for a target protein?

• Perform molecular dynamics refinement
• Select one or more suitable template structures
• Run Ramachandran plot analysis
• Optimize side-chain rotamers

Correct Answer: Select one or more suitable template structures

Q4. Which experimental feature of a template structure most directly affects its suitability for homology modeling?

• The protein’s expression host
• X-ray crystallographic resolution and R-factor
• The journal in which the structure was published
• The protein’s isoelectric point (pI)

Correct Answer: X-ray crystallographic resolution and R-factor

Q5. Which method is particularly powerful for detecting remote homologs via profile–profile comparison during template search?

• Basic BLAST (blastp)
• Simple pairwise Needleman–Wunsch alignment
• Hidden Markov Model-based tools (e.g., HHpred/HHsearch)
• GC-content analysis

Correct Answer: Hidden Markov Model-based tools (e.g., HHpred/HHsearch)

Q6. MODELLER builds comparative models primarily by which approach?

• De novo folding using physics-based force fields exclusively
• Satisfaction of spatial restraints derived from template structures
• Random conformational sampling without restraints
• Threading into all known folds without alignment

Correct Answer: Satisfaction of spatial restraints derived from template structures

Q7. What is the most common strategy to predict side-chain conformations in a homology model?

• Assign side chains arbitrarily from a single template without optimization
• Use rotamer libraries and rotamer optimization
• Replace all side chains with alanine to avoid clashes
• Ignore side chains altogether because they are unimportant

Correct Answer: Use rotamer libraries and rotamer optimization

Q8. Which algorithmic approach is widely used for accurate loop modeling and closure?

• Blind Monte Carlo with no closure constraint
• Kinematic closure (KIC) and related loop-closure algorithms
• Simple linear interpolation of backbone coordinates
• Replacing loops with poly-glycine segments only

Correct Answer: Kinematic closure (KIC) and related loop-closure algorithms

Q9. What does a Ramachandran plot evaluate when validating a protein model?

• Occupancy of metal-binding sites
• Distribution of backbone phi (φ) and psi (ψ) dihedral angles
• Hydrogen bond energies of side chains
• Solvent-accessible surface area of residues

Correct Answer: Distribution of backbone phi (φ) and psi (ψ) dihedral angles

Q10. Root-mean-square deviation (RMSD) between a model and a template measures what?

• The percentage of identical residues in the alignment
• The average atomic positional deviation between equivalent atoms
• The difference in molecular weight between model and template
• The electrostatic potential difference across the protein

Correct Answer: The average atomic positional deviation between equivalent atoms

Q11. MolProbity is a validation tool primarily used to assess which aspects of a model?

• Sequence alignment accuracy
• Steric clashes, rotamer outliers, and geometric quality
• Docking scores for ligands
• Predicted binding free energy

Correct Answer: Steric clashes, rotamer outliers, and geometric quality

Q12. Why is energy minimization or short molecular dynamics often applied after initial model building?

• To change the protein fold to a completely different topology
• To remove steric clashes and relax local geometry consistent with the force field
• To increase the sequence identity with the template
• To reduce the number of hydrogen bonds arbitrarily

Correct Answer: To remove steric clashes and relax local geometry consistent with the force field

Q13. What is an advantage of using multiple templates in comparative modeling?

• It always increases the global RMSD compared to a single template
• It can improve local model accuracy by combining complementary template regions
• It eliminates the need for alignment between target and templates
• It guarantees a correct prediction of ligand binding modes

Correct Answer: It can improve local model accuracy by combining complementary template regions

Q14. Threading or fold-recognition methods are especially useful when:

• Sequence identity to available templates is very high (>80%)
• No clear templates exist and sequence identity to known structures is low
• The protein is entirely disordered with no secondary structure
• Only transmembrane helices are present and no globular domains

Correct Answer: No clear templates exist and sequence identity to known structures is low

Q15. In template-target alignments, “coverage” refers to:

• The fraction of experimental studies that validated the template
• The percentage of target residues that are aligned to the template
• The browser compatibility of the homology modeling server
• The number of secondary structure elements in the template

Correct Answer: The percentage of target residues that are aligned to the template

Q16. Which of the following is a commonly used molecular mechanics force field for model refinement?

• BLAST
• AMBER
• HHpred
• PSIPRED

Correct Answer: AMBER

Q17. What is a typical approach to resolve side-chain steric clashes after initial modeling?

• Ignore clashes because they don’t affect model quality
• Use rotamer optimization followed by local minimization
• Randomly mutate residues until clashes disappear
• Replace all side chains with glycine

Correct Answer: Use rotamer optimization followed by local minimization

Q18. Which limitation is commonly associated with homology models?

• They are always more accurate than experimental structures
• They often have lower accuracy in long loop regions or untemplated segments
• They cannot provide any insight into active site geometry
• They eliminate the need for any further experimental validation

Correct Answer: They often have lower accuracy in long loop regions or untemplated segments

Q19. The DOPE score used by MODELLER is best described as:

• An experimental thermodynamic measurement of folding enthalpy
• A statistical potential where lower scores indicate more native-like models
• A direct measure of sequence identity to the template
• A count of hydrogen bonds in the model

Correct Answer: A statistical potential where lower scores indicate more native-like models

Q20. Which tool is commonly used to predict secondary structure to improve sequence–structure alignments during modeling?

• PSIPRED
• ClustalW without secondary structure input
• DOCK
• AutoDock Vina

Correct Answer: PSIPRED

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