This set of Bioinformatics Multiple Choice Questions & Answers (MCQs) focuses on “Ab Initio Protein Structural Prediction & Homology Modeling”.
1. Which of the following is untrue about homology modeling?
a) Homology modeling predicts protein structures based on sequence homology with known structures
b) It is also known as comparative modeling
c) The principle behind it is that if two proteins share a high enough sequence similarity, they are likely to have very similar three-dimensional structures
d) It doesn’t involve the evolutionary distances anywhere
Explanation: As the name suggests, homology modeling predicts protein structures based on sequence homology with known structures. Homology modeling produces an all-atom model based on alignment with template proteins.
2. Which of the following is untrue about template Selection Step?
a) The first step in protein structural modeling is to select appropriate structural templates
b) This forms the foundation for rest of the modeling process
c) There is no use of heuristic alignment search programs
d) The template selection involves searching the Protein Data Bank (PDB) for homologous proteins with determined structures
Explanation: The search can be performed using a heuristic pair wise alignment search program such as BLAST or FASTA. However, the use of dynamic programming based search programs such as SEARCH or ScanPS can result in more sensitive search results. The relatively small size of the structural database means that the search time using the exhaustive method is still within reasonable limits, while giving a more sensitive result to ensure the best possible similarity hits.
3. Which of the following is untrue about Sequence Alignment Step?
a) Once the structure with the highest sequence similarity is identified as a template, the full-length sequences of the template and target proteins need to be realigned using refined alignment algorithms to obtain optimal alignment
b) The realignment is the most critical step in homology modeling
c) The realignment directly affects the quality of the final model
d) Errors made in the alignment step can be corrected in the following modeling steps
Explanation: Incorrect alignment at this stage leads to incorrect designation of homologous residues and therefore to incorrect structural models. Errors made in the alignment step cannot be corrected in the following modeling steps. Therefore, the best possible multiple alignment algorithms, such as Praline and T-Coffee should be used for this purpose.
4. Which of the following is untrue about Backbone Model Building Step?
a) Once optimal alignment is achieved, residues in the aligned regions of the target protein can assume a similar structure as the template proteins
b) Coordinates of the corresponding residues of the template proteins can be simply copied onto the target protein
c) If the two residues differ, everything other than the backbone atoms can be copied
d) If the two aligned residues are identical, coordinates of the side chain atoms are copied along with the main chain atoms
Explanation: Option “Once optimal alignment is achieved, residues in the aligned regions of the target protein can assume a similar structure as the template proteins” and “Coordinates of the corresponding residues of the template proteins can be simply copied onto the target protein” mean the same. If the two residues differ, only the backbone atoms can be copied. The side chain atoms are rebuilt in a subsequent procedure.
In backbone modeling, it is simplest to use only one template structure. The structure with the best quality and highest resolution is normally chosen if multiple options are available.
5. Which of the following is untrue about Loop Modeling Step?
a) In the sequence alignment for modeling, there are often regions caused by insertions and deletions producing gaps in sequence alignment
b) In the sequence alignment for modeling, there are no regions producing gaps in sequence alignment
c) The gaps cannot be directly modeled
d) Loop modeling is required for closing the gaps requires
Explanation: Closing the gaps requires loop modeling, which is a very difficult problem in homology modeling and is also a major source of error. Loop modeling can be considered a mini–protein modeling problem by itself. Unfortunately, there are no mature methods available that can model loops reliably. Currently, there are two main techniques used to approach the problem: the database searching method and the ab initio method.
6. The procedure begins by measuring the orientation and distance of the anchor regions in the stems and searching PDB for segments of the same length that also match the above endpoint conformation.
Explanation: Usually, many different alternative segments that fit the endpoints of the stems are available. The best loop can be selected based on sequence similarity as well as minimal steric clashes with the neighboring parts of the structure. The conformation of the best matching fragments is then copied onto the anchoring points of the stems.
7. Which of the following is untrue about specialized programs for loop modeling?
a) PETRA is a web server that models loops using the database approach
b) FREAD is a web server that models loops using the database approach
c) CODA is a web server that uses a consensus method based on the prediction results from FREAD and PETRA
d) For loops of three to eight residues, CODA uses consensus conformation of both methods
Explanation: PETRA is a web server that uses the ab initio method to model loops. For nine to thirty residues, CODA uses FREAD prediction only.
8. In Side Chain Refinement step, A side chain can be built by searching every possible conformation at every torsion angle of the side chain to select the one that has the lowest interaction energy with neighboring atoms.
Explanation: However, this approach is computationally prohibitive in most cases. In fact, most current side chain prediction programs use the concept of rotamers, which are favored side chain torsion angles extracted from known protein crystal structures. In prediction of side chain conformation, only the possible rotamers with the lowest interaction energy with nearby atoms are selected.
9. In the step of Model Refinement Using Energy Function, the structural irregularities can be corrected by applying the energy minimization procedure on the entire model, which moves the atoms in such a way that the overall conformation has the lowest energy potential.
Explanation: In these loop modeling and side chain modeling steps, potential energy calculations are applied to improve the model. However, this does not guarantee that the entire raw homology model is free of structural irregularities such as unfavorable bond angles, bond lengths, or close atomic contacts. There, this step is used. The goal of energy minimization is to relieve steric collisions and strains without significantly altering the overall structure.
10. Energy minimization has to be used with caution because excessive energy minimization often moves residues away from their correct positions.
Explanation: Only limited energy minimization is recommended (a few hundred iterations) to remove major errors, such as short bond distances and close atomic clashes. Key conserved residues and those involved in cofactor binding have to be restrained if necessary during the process.
11. Which of the following is untrue about Ab initio prediction?
a) The limited knowledge of protein folding forms the basis of ab initio prediction
b) The ab initio prediction method attempts to produce all-atom protein models based on sequence information alone without the aid of known protein structures
c) The ab initio prediction method attempts to produce all-atom protein models based on sequence information alone with some aid of known protein structures
d) The perceived advantage of this method is that predictions are not restricted by known folds and that novel protein folds can be identified
Explanation: Alongside the advantages, because the physicochemical laws governing protein folding are not yet well understood, the energy functions used in the ab initio prediction are, at present, rather inaccurate. The folding problem remains one of the greatest challenges in bioinformatics today.
12. The prediction programs are thus designed using the energy minimization principle.
Explanation: Current ab initio algorithms are not yet able to accurately simulate the protein folding process. They work by using some type of heuristics. Because the native state of a protein structure is near energy minimum, the prediction programs are thus designed using the energy minimization principle.
13. Searching for a fold with the absolute minimum energy may not be valid in reality.
Explanation: These algorithms search for every possible conformation to find the one with the lowest global energy. However, searching for a fold with the absolute minimum energy may not be valid in reality. This contributes to one of the fundamental flaws of this approach. In addition, searching for all possible structural conformations is not yet computationally feasible.
14. Rosetta is a web server that predicts protein three-dimensional conformations using the ab initio method.
Explanation: This in fact relies on a “mini-threading” method. The method first breaks down the query sequence into many very short segments (three to nine residues) and predict the secondary structure of the small segments using a Hidden Markov model–based program, HMMSTR.
15. In Rosetta, The segments with assigned _______ structures are subsequently assembled into a ______ dimensional configuration.
a) primary, three
b) secondary, three
c) secondary, two
d) primary, three
Explanation: Through random combinations of the fragments, a large number of models are built and their overall energy potentials calculated. The conformation with the lowest global free energy is chosen as the best model.
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