Podcast
Questions and Answers
Fold recognition involves the building of a crude model by replacing aligned residues in a template structure with those in the query.
Fold recognition involves the building of a crude model by replacing aligned residues in a template structure with those in the query.
True
The structural database is not utilized in pairwise energy-based methods for thread matching.
The structural database is not utilized in pairwise energy-based methods for thread matching.
False
Aligning the query sequence with structural folds is a secondary step in the fold recognition process.
Aligning the query sequence with structural folds is a secondary step in the fold recognition process.
False
Energy-based criteria are used to find the matching structural fold during the threading process.
Energy-based criteria are used to find the matching structural fold during the threading process.
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Calculating the energy of the raw model is performed before aligning the query sequence in fold recognition.
Calculating the energy of the raw model is performed before aligning the query sequence in fold recognition.
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Homology modeling is based on the principle that structure is more conserved than sequence.
Homology modeling is based on the principle that structure is more conserved than sequence.
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A sequence identity of approximately 15% guarantees a highly accurate homology model.
A sequence identity of approximately 15% guarantees a highly accurate homology model.
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If no reliable template is available for homology modeling, one must resort to fold recognition or ab initio prediction.
If no reliable template is available for homology modeling, one must resort to fold recognition or ab initio prediction.
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Distantly related sequences can still fold into similar structures despite having low sequence identity.
Distantly related sequences can still fold into similar structures despite having low sequence identity.
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The quality of a homology model depends solely on the length of the target protein.
The quality of a homology model depends solely on the length of the target protein.
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The total number of folds in the SCOP database is irrelevant to homology modeling.
The total number of folds in the SCOP database is irrelevant to homology modeling.
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A sequence identity of over 40% is considered within the safe homology modeling zone.
A sequence identity of over 40% is considered within the safe homology modeling zone.
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Homology modeling is the least accurate 3D prediction approach compared to others.
Homology modeling is the least accurate 3D prediction approach compared to others.
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In fold recognition (threading), the protein sequence is matched against a collection of known structures to find the optimal structural fold using primarily energy-based methods.
In fold recognition (threading), the protein sequence is matched against a collection of known structures to find the optimal structural fold using primarily energy-based methods.
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During the threading process, a crude model for the target sequence is created by aligning residues of the query sequence with the respective residues of a pre-determined template structure.
During the threading process, a crude model for the target sequence is created by aligning residues of the query sequence with the respective residues of a pre-determined template structure.
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The distance used in energy calculations during threading is represented by the variable 'l', which must always be less than 10.
The distance used in energy calculations during threading is represented by the variable 'l', which must always be less than 10.
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Pairwise energy-based methods in fold recognition are solely dependent on structural folds and do not involve any sequence alignment.
Pairwise energy-based methods in fold recognition are solely dependent on structural folds and do not involve any sequence alignment.
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Energy calculations in fold recognition can be accurately derived only from a single known structure.
Energy calculations in fold recognition can be accurately derived only from a single known structure.
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MODELLER constructs models by satisfying the spatial restraints of the C α - C α bond lengths and angles, but does not consider van der Waals interactions.
MODELLER constructs models by satisfying the spatial restraints of the C α - C α bond lengths and angles, but does not consider van der Waals interactions.
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SWISS-MODEL is a protein structure homology modeling server that operates in a fully automated fashion.
SWISS-MODEL is a protein structure homology modeling server that operates in a fully automated fashion.
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Model validation checks are only necessary for verifying the quality of the template structure, not the derived model.
Model validation checks are only necessary for verifying the quality of the template structure, not the derived model.
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QMEAN is a model validation program specifically designed to estimate the quality of protein structure models by evaluating torsion angles and solvation.
QMEAN is a model validation program specifically designed to estimate the quality of protein structure models by evaluating torsion angles and solvation.
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Fold recognition through threading generates fully refined atomic models for the protein query sequence.
Fold recognition through threading generates fully refined atomic models for the protein query sequence.
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Energy-based methods in pairwise threading find the best matching structural fold by searching for protein sequences in a structural database based on energy criteria.
Energy-based methods in pairwise threading find the best matching structural fold by searching for protein sequences in a structural database based on energy criteria.
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The high rate of false positives in folding recognition indicates a low accuracy in predicting the correct protein fold when based on the existing database.
The high rate of false positives in folding recognition indicates a low accuracy in predicting the correct protein fold when based on the existing database.
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Verify3D and PROCHECK are examples of programs used specifically for fold recognition and threading.
Verify3D and PROCHECK are examples of programs used specifically for fold recognition and threading.
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Normality checks in model validation include evaluations of the distributions of polar and apolar residues.
Normality checks in model validation include evaluations of the distributions of polar and apolar residues.
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Homology modeling can be performed even if there are no suitable template structures available.
Homology modeling can be performed even if there are no suitable template structures available.
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Ab initio prediction is limited to predicting protein structures when homology modeling and fold recognition methods are not applicable.
Ab initio prediction is limited to predicting protein structures when homology modeling and fold recognition methods are not applicable.
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The lowest energy fold does not necessarily indicate the structurally most compatible fold of a protein.
The lowest energy fold does not necessarily indicate the structurally most compatible fold of a protein.
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I-TASSER is recognized as the number one server for protein structure prediction by the CASP evaluation.
I-TASSER is recognized as the number one server for protein structure prediction by the CASP evaluation.
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Robetta utilizes a purely theoretical approach without relying on any existing software for protein structure predictions.
Robetta utilizes a purely theoretical approach without relying on any existing software for protein structure predictions.
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CASP is a competition that provides an objective evaluation of prediction methods based on published protein structures.
CASP is a competition that provides an objective evaluation of prediction methods based on published protein structures.
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CAMEO assesses new protein structures on a weekly basis by sending registered prediction servers challenging requests.
CAMEO assesses new protein structures on a weekly basis by sending registered prediction servers challenging requests.
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Rosetta is a software suite specifically designed for predicting only protein folding mechanisms.
Rosetta is a software suite specifically designed for predicting only protein folding mechanisms.
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Ab initio prediction approaches have seen significant success in consistently obtaining correct protein structures.
Ab initio prediction approaches have seen significant success in consistently obtaining correct protein structures.
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Levinthal's paradox states that a random folding of a 100 residue protein would take approximately $1.6 * 10^{21}$ years.
Levinthal's paradox states that a random folding of a 100 residue protein would take approximately $1.6 * 10^{21}$ years.
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Anfinsen's thermodynamic hypothesis claims that the native structure of a protein is thermodynamically unstable.
Anfinsen's thermodynamic hypothesis claims that the native structure of a protein is thermodynamically unstable.
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The hydrophobic collapse model suggests that protein folding occurs in an expanded volume, facilitating a broad conformational search.
The hydrophobic collapse model suggests that protein folding occurs in an expanded volume, facilitating a broad conformational search.
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Free energy of folding is expressed as $ riangle G_{fold} = riangle H + T riangle S$.
Free energy of folding is expressed as $ riangle G_{fold} = riangle H + T riangle S$.
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The tertiary structure of a protein becomes more unstable when the sum of non-covalent weak interactions increases.
The tertiary structure of a protein becomes more unstable when the sum of non-covalent weak interactions increases.
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NMR spectroscopy provides information about the very fast motions and transition states of proteins.
NMR spectroscopy provides information about the very fast motions and transition states of proteins.
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Molecular dynamics allows for the assessment of slow large-scale motions occurring over time scales greater than one millisecond.
Molecular dynamics allows for the assessment of slow large-scale motions occurring over time scales greater than one millisecond.
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The Framework model posits that the secondary structure folds last into a tertiary structure.
The Framework model posits that the secondary structure folds last into a tertiary structure.
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Databases like ModBase contain predictions for approximately 3.8 million protein models.
Databases like ModBase contain predictions for approximately 3.8 million protein models.
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The nucleation-condensation model describes a protein folding mechanism where secondary and tertiary structures form concurrently.
The nucleation-condensation model describes a protein folding mechanism where secondary and tertiary structures form concurrently.
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The term 'denaturation' refers to the formation of new bonds with solvent instead of protein atoms.
The term 'denaturation' refers to the formation of new bonds with solvent instead of protein atoms.
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The time scale of aromatic ring flipping can be observed in the picosecond to microsecond range.
The time scale of aromatic ring flipping can be observed in the picosecond to microsecond range.
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The Molecular Dynamics Extended Library is one of the databases dedicated to studying the dynamics of protein folding.
The Molecular Dynamics Extended Library is one of the databases dedicated to studying the dynamics of protein folding.
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In fold recognition, the query sequence is aligned with each structural fold at the amino acid level before building a crude model for the target sequence.
In fold recognition, the query sequence is aligned with each structural fold at the amino acid level before building a crude model for the target sequence.
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During the threading process, calculating the energy of the raw model occurs before aligning the query sequence with structural folds.
During the threading process, calculating the energy of the raw model occurs before aligning the query sequence with structural folds.
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Fold recognition relies on pairwise energy calculations that strictly depend on the sequence profiles of the proteins being analyzed.
Fold recognition relies on pairwise energy calculations that strictly depend on the sequence profiles of the proteins being analyzed.
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The crude model created in fold recognition includes the original residues from the template structure rather than those from the query sequence.
The crude model created in fold recognition includes the original residues from the template structure rather than those from the query sequence.
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Energy-based criteria in fold recognition are applied to assess the compatibility of a protein's query sequence with known structural folds in a database.
Energy-based criteria in fold recognition are applied to assess the compatibility of a protein's query sequence with known structural folds in a database.
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A sequence identity of less than 25% generally allows for reliable template identification.
A sequence identity of less than 25% generally allows for reliable template identification.
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The resolution of the template structure is an irrelevant factor when selecting a template for homology modeling.
The resolution of the template structure is an irrelevant factor when selecting a template for homology modeling.
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More than one possible template may be identified, requiring multiple criteria for the selection of the final template.
More than one possible template may be identified, requiring multiple criteria for the selection of the final template.
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Profile-based searches are typically less sensitive than standard sequence-similarity searches.
Profile-based searches are typically less sensitive than standard sequence-similarity searches.
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If no reliable template is identified, fold recognition methods cannot be applied.
If no reliable template is identified, fold recognition methods cannot be applied.
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In pairwise energy-based methods of fold recognition, the protein sequence is compared against a structural database to identify the optimal structural fold using primarily energy-based criteria regardless of sequence alignment.
In pairwise energy-based methods of fold recognition, the protein sequence is compared against a structural database to identify the optimal structural fold using primarily energy-based criteria regardless of sequence alignment.
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Distance in energy calculations during threading is denoted by the variable 'l', which may vary based on specific criteria rather than being restricted to being greater than 10.
Distance in energy calculations during threading is denoted by the variable 'l', which may vary based on specific criteria rather than being restricted to being greater than 10.
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The energy of the crude model in fold recognition is calculated after the alignment of the query sequence with the structural folds in the fold library.
The energy of the crude model in fold recognition is calculated after the alignment of the query sequence with the structural folds in the fold library.
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Fold recognition through threading is solely based on matching protein sequences to structural folds without considering the molecular energy of the interactions during the folding process.
Fold recognition through threading is solely based on matching protein sequences to structural folds without considering the molecular energy of the interactions during the folding process.
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A successful threading process guarantees a high-quality structural model regardless of the underlying energy criteria used during the comparison.
A successful threading process guarantees a high-quality structural model regardless of the underlying energy criteria used during the comparison.
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Homology modeling relies on the principle that structure is more conserved than sequence.
Homology modeling relies on the principle that structure is more conserved than sequence.
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A sequence identity of approximately 15% ensures a high level of accuracy in homology modeling.
A sequence identity of approximately 15% ensures a high level of accuracy in homology modeling.
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The SCOP database is utilized to count the total number of protein folds but doesn't relate to homology modeling.
The SCOP database is utilized to count the total number of protein folds but doesn't relate to homology modeling.
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For reliable homology modeling, the sequence identity between the target protein and template must exceed 25%.
For reliable homology modeling, the sequence identity between the target protein and template must exceed 25%.
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Fold recognition is the least accurate method for 3D protein structure prediction compared to homology modeling.
Fold recognition is the least accurate method for 3D protein structure prediction compared to homology modeling.
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If homology modeling templates are unavailable, one must use fold recognition or de novo prediction methods.
If homology modeling templates are unavailable, one must use fold recognition or de novo prediction methods.
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Models generated from homology modeling are only as good as the sequence similarity between target and template proteins.
Models generated from homology modeling are only as good as the sequence similarity between target and template proteins.
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The principle of distantly related sequences folding into similar structures invalidates the necessity of sequence alignment in homology modeling.
The principle of distantly related sequences folding into similar structures invalidates the necessity of sequence alignment in homology modeling.
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Ab initio prediction is effective in generating structures with the aid of existing templates.
Ab initio prediction is effective in generating structures with the aid of existing templates.
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The CASP competition is held annually to assess the performance of protein structure prediction methods.
The CASP competition is held annually to assess the performance of protein structure prediction methods.
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Robetta uses both homology modeling and ab initio predictions as part of its structural prediction process.
Robetta uses both homology modeling and ab initio predictions as part of its structural prediction process.
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CAMEO assesses new structures in the PDB on a yearly basis by sending requests for challenging predictions.
CAMEO assesses new structures in the PDB on a yearly basis by sending requests for challenging predictions.
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I-TASSER does not incorporate any form of threading in its prediction methodology.
I-TASSER does not incorporate any form of threading in its prediction methodology.
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The successful application of ab initio prediction methods has significantly increased in terms of acquiring accurate protein structures.
The successful application of ab initio prediction methods has significantly increased in terms of acquiring accurate protein structures.
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Rosetta is exclusively used for predicting protein folding mechanisms, without any capability for protein structure design.
Rosetta is exclusively used for predicting protein folding mechanisms, without any capability for protein structure design.
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The lowest energy fold generally represents the least compatible structural fold for a protein.
The lowest energy fold generally represents the least compatible structural fold for a protein.
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Levinthal's paradox implies that a 100 residue protein would fold randomly in approximately $5 * 10^{34}$ seconds.
Levinthal's paradox implies that a 100 residue protein would fold randomly in approximately $5 * 10^{34}$ seconds.
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Anfinsen's thermodynamic hypothesis states that the folding of a protein is influenced solely by its amino acid sequence and not by environmental conditions.
Anfinsen's thermodynamic hypothesis states that the folding of a protein is influenced solely by its amino acid sequence and not by environmental conditions.
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The hydrophobic collapse model suggests that protein folding occurs by expanding the protein in a larger volume before compacting.
The hydrophobic collapse model suggests that protein folding occurs by expanding the protein in a larger volume before compacting.
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The nucleation-growth model accounts for folding intermediates and is widely accepted in explaining protein folding mechanisms.
The nucleation-growth model accounts for folding intermediates and is widely accepted in explaining protein folding mechanisms.
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Free energy of folding can be mathematically represented as $ΔG_{fold} = ΔH + TΔS$.
Free energy of folding can be mathematically represented as $ΔG_{fold} = ΔH + TΔS$.
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The tertiary structure of a protein is considered marginally less stable than its unfolded state, with variations between 10-80 kJ/mol.
The tertiary structure of a protein is considered marginally less stable than its unfolded state, with variations between 10-80 kJ/mol.
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NMR spectroscopy is capable of describing both very fast motions and the energetics of protein dynamics in detail.
NMR spectroscopy is capable of describing both very fast motions and the energetics of protein dynamics in detail.
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Molecular dynamics provides insight into energetics, amplitudes, and time scales of local motions but does not cover slow large-scale motions.
Molecular dynamics provides insight into energetics, amplitudes, and time scales of local motions but does not cover slow large-scale motions.
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The Framework model suggests that the tertiary structure folds first, which is contrary to observations of folding mechanisms.
The Framework model suggests that the tertiary structure folds first, which is contrary to observations of folding mechanisms.
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The Molecular Movements Database (MolMovDB) is a specialized database for tracking solvent interactions during protein folding.
The Molecular Movements Database (MolMovDB) is a specialized database for tracking solvent interactions during protein folding.
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In the context of protein dynamics, the interior atoms are less restricted in movement compared to those near the surface.
In the context of protein dynamics, the interior atoms are less restricted in movement compared to those near the surface.
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Denaturation refers to the reformation of bonds between protein atoms after being disrupted by environmental factors.
Denaturation refers to the reformation of bonds between protein atoms after being disrupted by environmental factors.
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High-resolution X-ray crystallography can describe flexible regions of proteins accurately.
High-resolution X-ray crystallography can describe flexible regions of proteins accurately.
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The Molecular Dynamics Extended Library (MoDEL) is one of the databases primarily utilized for studying static protein structures.
The Molecular Dynamics Extended Library (MoDEL) is one of the databases primarily utilized for studying static protein structures.
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The distance variable 'l' used in energy calculations during threading must always be greater than 10.
The distance variable 'l' used in energy calculations during threading must always be greater than 10.
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The process of fold recognition involves creating a fully refined atomic model for the protein query sequence.
The process of fold recognition involves creating a fully refined atomic model for the protein query sequence.
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Pairwise energy-based methods in thread recognition exclusively rely on sequence alignment without considering structural databases.
Pairwise energy-based methods in thread recognition exclusively rely on sequence alignment without considering structural databases.
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In fold recognition, energy calculations are exclusively accurate when derived from a collection of known structures.
In fold recognition, energy calculations are exclusively accurate when derived from a collection of known structures.
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The crude model for the target sequence is built before aligning the query sequence with structural folds in fold recognition.
The crude model for the target sequence is built before aligning the query sequence with structural folds in fold recognition.
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In fold recognition, aligning the query sequence occurs as a preliminary step before utilizing energy-based criteria for structural matching.
In fold recognition, aligning the query sequence occurs as a preliminary step before utilizing energy-based criteria for structural matching.
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Building a crude model during fold recognition involves substituting aligned residues in the template with those from the target sequence.
Building a crude model during fold recognition involves substituting aligned residues in the template with those from the target sequence.
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Calculating the energy of the raw model is an insignificant part of the threading process in fold recognition.
Calculating the energy of the raw model is an insignificant part of the threading process in fold recognition.
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The energy-based methods used in fold recognition operate primarily using sequence alignment followed by a structural database search.
The energy-based methods used in fold recognition operate primarily using sequence alignment followed by a structural database search.
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A sequence identity of less than 25% is optimal for identifying a reliable template using standard sequence-similarity searches.
A sequence identity of less than 25% is optimal for identifying a reliable template using standard sequence-similarity searches.
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The coverage between the template and query sequences is an unimportant factor in selecting the final template for modeling.
The coverage between the template and query sequences is an unimportant factor in selecting the final template for modeling.
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The performance of pairwise energy-based methods in fold recognition is independent of the structural database used in matching.
The performance of pairwise energy-based methods in fold recognition is independent of the structural database used in matching.
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Profile-based searches are generally less sensitive compared to standard sequence-similarity searches.
Profile-based searches are generally less sensitive compared to standard sequence-similarity searches.
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In fold recognition methods, a reliable template can always be identified when the sequence identity is greater than 25%.
In fold recognition methods, a reliable template can always be identified when the sequence identity is greater than 25%.
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More than one possible template may be identified, but diverse criteria must be considered for selecting the final one.
More than one possible template may be identified, but diverse criteria must be considered for selecting the final one.
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Homology modeling is considered the least accurate 3D prediction approach available.
Homology modeling is considered the least accurate 3D prediction approach available.
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The twilight zone in homology modeling signifies a sequence identity range of approximately 25% to 40%.
The twilight zone in homology modeling signifies a sequence identity range of approximately 25% to 40%.
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If no suitable templates are available, fold recognition is the only alternative for model building.
If no suitable templates are available, fold recognition is the only alternative for model building.
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A sequence identity of approximately 15% suggests that the proteins will likely adopt completely different structures.
A sequence identity of approximately 15% suggests that the proteins will likely adopt completely different structures.
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The quality of a homology model is solely determined by the length of the target protein, not by sequence identity.
The quality of a homology model is solely determined by the length of the target protein, not by sequence identity.
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Energy-based methods in fold recognition disregard structural folds and only utilize sequence information.
Energy-based methods in fold recognition disregard structural folds and only utilize sequence information.
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A sequence identity greater than 40% is categorized within the safe homology modeling zone.
A sequence identity greater than 40% is categorized within the safe homology modeling zone.
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Distantly related sequences often exhibit a high similarity in the protein structures they adopt.
Distantly related sequences often exhibit a high similarity in the protein structures they adopt.
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Homology modeling programs like MODELLER rely on the C α - C α bond lengths but do not consider side-chain angles.
Homology modeling programs like MODELLER rely on the C α - C α bond lengths but do not consider side-chain angles.
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The SWISS-MODEL server provides an automated approach to protein structure homology modeling.
The SWISS-MODEL server provides an automated approach to protein structure homology modeling.
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Model validation checks are primarily concerned with the quality of the derived model and are not necessary for the template structure.
Model validation checks are primarily concerned with the quality of the derived model and are not necessary for the template structure.
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QMEAN evaluates model quality based on torsion angles and interactions, but ignores secondary structure agreement.
QMEAN evaluates model quality based on torsion angles and interactions, but ignores secondary structure agreement.
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Fold recognition (threading) is capable of generating fully refined atomic models for a given protein sequence.
Fold recognition (threading) is capable of generating fully refined atomic models for a given protein sequence.
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Energy-based methods in pairwise energy-based threading utilize a sequence database to find optimal structural folds.
Energy-based methods in pairwise energy-based threading utilize a sequence database to find optimal structural folds.
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The high rate of false positives in fold recognition indicates a strong reliability in predicting protein structures.
The high rate of false positives in fold recognition indicates a strong reliability in predicting protein structures.
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Normality checks in model validation include assessing the distributions of polar and apolar residues.
Normality checks in model validation include assessing the distributions of polar and apolar residues.
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Ab initio prediction approaches are utilized only when homology modeling techniques are applicable.
Ab initio prediction approaches are utilized only when homology modeling techniques are applicable.
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The protein structure homology modeling relies predominantly on the accuracy of the template structure.
The protein structure homology modeling relies predominantly on the accuracy of the template structure.
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Levinthal's paradox suggests that a protein with 100 residues and 3 conformations per residue would take approximately $1.6 * 10^{34}$ years to fold randomly.
Levinthal's paradox suggests that a protein with 100 residues and 3 conformations per residue would take approximately $1.6 * 10^{34}$ years to fold randomly.
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Anfinsen's thermodynamic hypothesis states that the stability of a protein's native structure is independent of the solvent conditions.
Anfinsen's thermodynamic hypothesis states that the stability of a protein's native structure is independent of the solvent conditions.
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The Nucleation-growth model accounts for folding intermediates during protein folding.
The Nucleation-growth model accounts for folding intermediates during protein folding.
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The Hydrophobic collapse model is characterized by protein folding beginning in a confined volume.
The Hydrophobic collapse model is characterized by protein folding beginning in a confined volume.
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A protein's folded state is considered marginally less stable than its unfolded state, with a stability difference of around 10-80 kJ/mol.
A protein's folded state is considered marginally less stable than its unfolded state, with a stability difference of around 10-80 kJ/mol.
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In molecular dynamics, the system's interactions are described using classical Newtonian principles.
In molecular dynamics, the system's interactions are described using classical Newtonian principles.
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The Framework model describes a protein folding mechanism that leads to the tertiary structure folding before the secondary structure.
The Framework model describes a protein folding mechanism that leads to the tertiary structure folding before the secondary structure.
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Normal mode analysis does not account for local movements or time scales of protein dynamics.
Normal mode analysis does not account for local movements or time scales of protein dynamics.
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Molecular Dynamics allows study of large-scale protein motions occurring over time scales under one millisecond.
Molecular Dynamics allows study of large-scale protein motions occurring over time scales under one millisecond.
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The average low energy structure in high resolution X-ray crystallography is adequate for capturing very flexible regions of proteins.
The average low energy structure in high resolution X-ray crystallography is adequate for capturing very flexible regions of proteins.
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All databases of dynamics, such as MoDEL, focus solely on predicting static structures of proteins without considering dynamic aspects.
All databases of dynamics, such as MoDEL, focus solely on predicting static structures of proteins without considering dynamic aspects.
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Energetically, the free energy of folding, represented as $ΔG_{fold} = ΔH - TΔS$, implies that higher structural stability results in lower entropy.
Energetically, the free energy of folding, represented as $ΔG_{fold} = ΔH - TΔS$, implies that higher structural stability results in lower entropy.
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The average time scale for motions in the interior of a protein is typically unrelated to the packing restraints.
The average time scale for motions in the interior of a protein is typically unrelated to the packing restraints.
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Study Notes
Models of Structures
- Key structures are modeled to understand biological function.
- Experimental structure is unavailable for many sequences.
- The number of protein entries increases.
Importance of Structure
- Experimental structure unavailable for most sequences.
- Number of entries (millions) increases over time.
- Significant growth of data sources.
- Swiss-Prot, PDB, and TREMBL are among the databases, providing increasing data since 2000.
Homology Modeling
- Structure is more conserved than sequence.
- Similar sequences have practically identical structures.
- Exp: haloalkane dehalogenase LinB (PDB-ID 1iz7) and haloalkane dehalogenase DhaA (PDB-ID 1cqw), with ~50% sequence identity.
- Distantly related sequences can still have similar folds.
- Exp: haloalkane dehalogenase LinB (PDB-ID 1iz7) and chloroperoxidase L (PDB-ID 1a88), with approximately 15% sequence identity.
- Number of folds in SCOP database significantly increases year by year.
- Atomic-resolution model of target protein based on similar protein's 3D structure (template).
- Most accurate 3D prediction approach.
- If no reliable template → fold recognition or initial prediction.
- The quality of the model is dependent on the sequence identity.
- For shorter proteins, sequence identity should be above 25%; for longer proteins, sequence identity should be above 40%.
- Shows the steps of homology modeling.
- Target sequence.
- Database search.
- Selection of template.
- Sequence alignment.
- Model validation.
- Model optimization.
- Loop and side-chain modeling.
- Building model framework.
- Database search methods can contain errors.
- Sophisticated methods needed: Multiple sequence alignment, Profile-driven alignments and alignment correction based on template structure.
Model Validation
- Finished models contain errors.
- Error number mainly depends on the sequence identity between template and target.
- E.g. 90%: comparable accuracy to X-ray structures; 50-90%: larger local errors; <25%: often large errors.
- Number of errors in template structure affecting the validity of the model.
- Problems distant from the interest region can be ignored.
- The model iteration process can correct any errors identified during optimization, which requires running a shorter molecular dynamics simulation.
- Large mistakes in backbone conformation entail repetition of the entire process, often including different alignments or templates.
Homology Modeling Programs
- MODELLER: models structures by satisfying spatial restraints of Cα-Cα bond lengths, angles, side-chain dihedral angles and van der Waals interactions. Implemented as a webserver to calculate restraints from template structures. Available in different websites like ModWeb, GeneSilico, and Bioinformatic toolkit.
- SWISS-MODEL: fully automated web server for protein structure homology modeling, performing a sequence search and finding the best matching template and displaying model information such as sequences identity, E-values, QMEAN Z-score, residue ranges and model structure.
Model Validation Programs
- QMEAN: assesses protein structure models by evaluating torsion angles, solvation, and non-bonded interactions, and consistency between predicted and calculated secondary structure, and solvent accessibility. Provides global and local scores.
- Verify3B, ANOLEA, PROCHECK, WHATCHECK, and PROSA II are other frequently used tools for model validation.
Fold Recognition (Threading)
- Predicts protein fold by fitting its sequence into a structural database.
- Provides a rough approximation of overall topology of native structure (does not generate fully refined atomic models).
- Useful when no suitable template structures are available.
- Fails if the correct protein fold isn't in the database; has high rates of false positives.
- Pairwise energy-based methods are used to search structures.
- Structural fold alignment is performed on sequence profile level.
- Target sequence is modeled with template structure.
- Energies of raw models are calculated.
- Lowest energy fold represents the most compatible fold.
Ab Initio Prediction
- Generates protein structure using only physicochemical principles.
- Applied when homology modeling and fold recognition fail.
- Searches for global free-energy minimum; success rates are limited.
- Rosetta is a frequently used software suite for predicting and designing protein structures.
Hybrid 3D Structure Prediction Programs
- I-TASSER combines homology modeling, threading, and Ab initio to improve the prediction of protein structure on the server.
- Robetta also combines homology modeling and Ab initio methodologies and implements ROSETTA software.
Assessment of Prediction Methods
- CASP (Critical Assessment of Techniques for Protein Structure Prediction) is an international contest to objectively evaluate performance. Methods are evaluated based on blind protein predictions and compared to experimentally determined structures.
- CAMEO (Continuous Automated Model Evaluation) provides weekly evaluation of protein structures in PDB on the webserver. Multiple scores (e.g. normalized average IDDT) are considered.
Databases of Protein Models
- ModBase is a database of annotated protein models built using MODELLER program. It contains 38 million models for ~6.5 million unique sequences.
Protein Folding, Stability and Dynamics
- Levinthal's paradox highlights the impossibly long time for random protein folding.
- Anfinsen's thermodynamic hypothesis emphasizes that folding is determined by the amino acid sequence and solution conditions, not by the kinetic path.
- Folding often involves a combination of: 2˚ structure formation, hydrophobic collapse, nucleation, rearrangement, propagation and condensation.
- Nucleation-growth and nucleation-condensation models are proposed mechanisms of protein folding.
- Protein folding is dependent on energetics, such as enthalpy decrease and entropy increase.
- Tertiary structure and weak non-covalent interactions versus conformational entropy are key to determine stability.
- Protein denaturation disrupts weak interactions.
- Protein dynamics involves fluctuations and movement of atoms.
- NMR spectroscopy, high resolution X-ray crystallography, normal-mode analysis, and molecular dynamics approaches are crucial for studying protein dynamics.
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Description
This quiz explores the key concepts of biological structure modeling, emphasizing the understanding of protein functionality through structure. It also discusses the importance of databases like Swiss-Prot and PDB, alongside the principles of homology modeling and structural conservation in proteins.
