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Questions and Answers
Oligomerization interfaces generally have a surface area of less than 1400 Å2.
Oligomerization interfaces generally have a surface area of less than 1400 Å2.
False
In oligomerization, the proteins involved are typically denatured.
In oligomerization, the proteins involved are typically denatured.
False
The presence of 'hot-spot' residues in oligomeric interactions is primarily due to their frequent occurrence and evolutionary conservation.
The presence of 'hot-spot' residues in oligomeric interactions is primarily due to their frequent occurrence and evolutionary conservation.
True
Aggregates formed by proteins are always pathological and indicate disease.
Aggregates formed by proteins are always pathological and indicate disease.
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The nature of protein oligomers is strictly reversible in all cases.
The nature of protein oligomers is strictly reversible in all cases.
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Methods based on distance between interacting residues are not commonly used for interface analysis.
Methods based on distance between interacting residues are not commonly used for interface analysis.
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PDBsum provides information only about protein-protein interactions.
PDBsum provides information only about protein-protein interactions.
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The Voronoi diagram is a computational geometry method utilized in interface analysis.
The Voronoi diagram is a computational geometry method utilized in interface analysis.
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Hot spots in macromolecular complexes contribute minimally to the binding free energy.
Hot spots in macromolecular complexes contribute minimally to the binding free energy.
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The change in solvent accessible surface area can be used to define interfaces in macromolecular analysis.
The change in solvent accessible surface area can be used to define interfaces in macromolecular analysis.
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PISA, MolSurfer, and PIC are tools used to analyze the interface of given macromolecular complexes.
PISA, MolSurfer, and PIC are tools used to analyze the interface of given macromolecular complexes.
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Knowledge of hot spots has no implications for drug development.
Knowledge of hot spots has no implications for drug development.
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All three approaches for interface definition provide significantly different results.
All three approaches for interface definition provide significantly different results.
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Hot spots in protein interactions are typically found in loosely packed regions at the interface.
Hot spots in protein interactions are typically found in loosely packed regions at the interface.
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Alanine scanning mutagenesis is a method used to identify hot spots based on changes in binding affinity.
Alanine scanning mutagenesis is a method used to identify hot spots based on changes in binding affinity.
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Energy-based methods for predicting hot spots do not consider changes in binding free energy (∆∆Gbind).
Energy-based methods for predicting hot spots do not consider changes in binding free energy (∆∆Gbind).
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Point mutations can include substitutions, insertions, and deletions of nucleotides in DNA.
Point mutations can include substitutions, insertions, and deletions of nucleotides in DNA.
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Missense mutations result in the introduction of a stop codon, leading to protein truncation.
Missense mutations result in the introduction of a stop codon, leading to protein truncation.
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The Human Genome Variation Society offers a comprehensive database of human mutations categorized by types.
The Human Genome Variation Society offers a comprehensive database of human mutations categorized by types.
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Silent mutations result in a change in the amino acid sequence of the protein.
Silent mutations result in a change in the amino acid sequence of the protein.
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Locus-specific databases generally contain a wide range of mutations across various genes.
Locus-specific databases generally contain a wide range of mutations across various genes.
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UniProtKB/Swiss-Prot is a source of low-quality protein entries with limited information on known sequence variants.
UniProtKB/Swiss-Prot is a source of low-quality protein entries with limited information on known sequence variants.
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The introduction of insertions or deletions can potentially lead to frameshift mutations.
The introduction of insertions or deletions can potentially lead to frameshift mutations.
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Missense mutations can only affect the stability of proteins, not their function.
Missense mutations can only affect the stability of proteins, not their function.
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The introduction of hydrophobic residues on the surface of a protein can decrease its aggregation.
The introduction of hydrophobic residues on the surface of a protein can decrease its aggregation.
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Glycine is known as the most flexible amino acid due to its unique backbone conformation.
Glycine is known as the most flexible amino acid due to its unique backbone conformation.
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Mutations that affect ligand transport can either enhance or hinder the movement of specific molecules.
Mutations that affect ligand transport can either enhance or hinder the movement of specific molecules.
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Protein dynamics are solely responsible for maintaining protein stability after translation.
Protein dynamics are solely responsible for maintaining protein stability after translation.
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Ile84Val and Ile50Val mutations lead to a significant increase in Ki, indicating a decrease in binding affinity.
Ile84Val and Ile50Val mutations lead to a significant increase in Ki, indicating a decrease in binding affinity.
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Short specific sequences known as Aggregation-prone regions (APRs) typically consist of 10-20 hydrophobic residues.
Short specific sequences known as Aggregation-prone regions (APRs) typically consist of 10-20 hydrophobic residues.
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Changes in charge and hydrophobicity within a protein can lead to altered folding and stability.
Changes in charge and hydrophobicity within a protein can lead to altered folding and stability.
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The mutations affecting folding primarily involve interactions such as salt bridges and hydrogen bonds.
The mutations affecting folding primarily involve interactions such as salt bridges and hydrogen bonds.
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Missense mutations can only cause loss of function and never result in improved binding or function.
Missense mutations can only cause loss of function and never result in improved binding or function.
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Binding energy can only be estimated using empirical methods.
Binding energy can only be estimated using empirical methods.
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Clustering-based scoring functions consider the presence of numerous similar solutions as an indication of correctness.
Clustering-based scoring functions consider the presence of numerous similar solutions as an indication of correctness.
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FastContact is an online tool designed to provide in-depth analysis of the nucleic acid chains only.
FastContact is an online tool designed to provide in-depth analysis of the nucleic acid chains only.
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Macromolecular interfaces are determined solely through experimental methods and cannot be predicted computationally.
Macromolecular interfaces are determined solely through experimental methods and cannot be predicted computationally.
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Two-stage ranking methods in macromolecular docking first apply an accurate function for the initial evaluation.
Two-stage ranking methods in macromolecular docking first apply an accurate function for the initial evaluation.
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Interface analysis provides insights into shape and chemical complementarity of macromolecular interactions.
Interface analysis provides insights into shape and chemical complementarity of macromolecular interactions.
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The contributions of individual residues to free energy are ignored in the analysis of macromolecular interactions.
The contributions of individual residues to free energy are ignored in the analysis of macromolecular interactions.
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The scoring functions used in macromolecular docking include empirical and force field-based methods among others.
The scoring functions used in macromolecular docking include empirical and force field-based methods among others.
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The mutation of highly conserved residues is likely to lead to destabilization or loss of function.
The mutation of highly conserved residues is likely to lead to destabilization or loss of function.
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Mutations in often variable residues typically have a significant impact on protein function.
Mutations in often variable residues typically have a significant impact on protein function.
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A mutation that introduces a charged residue in a neutral environment is likely to stabilize the protein.
A mutation that introduces a charged residue in a neutral environment is likely to stabilize the protein.
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Mutations in residues located in binding sites can alter biochemical activities such as catalysis.
Mutations in residues located in binding sites can alter biochemical activities such as catalysis.
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The Monte Carlo approach is used to predict the most favorable rotamer conformations for mutated residues.
The Monte Carlo approach is used to predict the most favorable rotamer conformations for mutated residues.
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Mutations causing a small residue to become a large residue may lead to steric clashes.
Mutations causing a small residue to become a large residue may lead to steric clashes.
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Desolvation penalties resulting from mutations are always destabilizing to the protein structure.
Desolvation penalties resulting from mutations are always destabilizing to the protein structure.
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Introduction of hydrophobic residues at the protein surface generally has a neutral effect.
Introduction of hydrophobic residues at the protein surface generally has a neutral effect.
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Proline or glycine mutations do not significantly affect the conformation of the protein.
Proline or glycine mutations do not significantly affect the conformation of the protein.
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The assessment of mutational effects involves comparing the energy states of mutant and native proteins.
The assessment of mutational effects involves comparing the energy states of mutant and native proteins.
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Oligomers typically exist in a native state, while aggregates consist of denatured proteins.
Oligomers typically exist in a native state, while aggregates consist of denatured proteins.
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Aggregates are always associated with pathological conditions and indicative of disease.
Aggregates are always associated with pathological conditions and indicative of disease.
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Hot-spot residues are located primarily at the edges of oligomerization interfaces.
Hot-spot residues are located primarily at the edges of oligomerization interfaces.
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The surface area of an oligomerization interface is typically less than 1400 Å2.
The surface area of an oligomerization interface is typically less than 1400 Å2.
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Aggregates can be reversible, while oligomers are often irreversible.
Aggregates can be reversible, while oligomers are often irreversible.
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The author-specified assembly in PDB files is always accurate and does not require verification.
The author-specified assembly in PDB files is always accurate and does not require verification.
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Experimental methods like gel filtration and native electrophoresis can aid in determining the oligomeric state of a protein.
Experimental methods like gel filtration and native electrophoresis can aid in determining the oligomeric state of a protein.
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Most proteins in the PDB exhibit only minimal crystal contacts, contributing less than 10% to the solvent accessible surface area.
Most proteins in the PDB exhibit only minimal crystal contacts, contributing less than 10% to the solvent accessible surface area.
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The use of predictive tools for determining macromolecular complex structures is not acknowledged in protein structure analysis.
The use of predictive tools for determining macromolecular complex structures is not acknowledged in protein structure analysis.
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Understanding the biological unit requires solely relying on the author-specified assembly without evaluating additional literature or methodologies.
Understanding the biological unit requires solely relying on the author-specified assembly without evaluating additional literature or methodologies.
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Obligate complexes function independently of their protomers.
Obligate complexes function independently of their protomers.
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Hetero-oligomers are more common than homo-oligomers in cellular proteins.
Hetero-oligomers are more common than homo-oligomers in cellular proteins.
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Approximately 75% of proteins in a cell exist in an oligomeric form.
Approximately 75% of proteins in a cell exist in an oligomeric form.
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Oligomerization enhances stability against denaturation by increasing the surface area.
Oligomerization enhances stability against denaturation by increasing the surface area.
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The process of cooperativity in proteins refers to uniform activity among all subunits during molecular interaction.
The process of cooperativity in proteins refers to uniform activity among all subunits during molecular interaction.
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In obligate complexes, individual subunits can retain some functional activity when not associated.
In obligate complexes, individual subunits can retain some functional activity when not associated.
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Oligomerization is evolutionarily favored due to the advantages it provides in terms of protein function.
Oligomerization is evolutionarily favored due to the advantages it provides in terms of protein function.
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Redundancy and error control are significant advantages of protein oligomerization.
Redundancy and error control are significant advantages of protein oligomerization.
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Homology-based methods can predict protein interactions based on close homologs with less than 40% sequence identity.
Homology-based methods can predict protein interactions based on close homologs with less than 40% sequence identity.
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The search space for flexible docking is characterized by a dimensionality less than that of rigid docking.
The search space for flexible docking is characterized by a dimensionality less than that of rigid docking.
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Soft docking methods utilize strict scoring functions to account for the rigidity of molecules during macromolecular docking.
Soft docking methods utilize strict scoring functions to account for the rigidity of molecules during macromolecular docking.
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An exhaustive search in macromolecular docking is computationally less expensive than stochastic methods.
An exhaustive search in macromolecular docking is computationally less expensive than stochastic methods.
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Macromolecular docking can efficiently predict the best bound state of interacting macromolecules without requiring prior knowledge of binding sites.
Macromolecular docking can efficiently predict the best bound state of interacting macromolecules without requiring prior knowledge of binding sites.
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In flexible docking, both interacting macromolecules are treated as rigid structures.
In flexible docking, both interacting macromolecules are treated as rigid structures.
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A scoring function in macromolecular docking is solely based on empirical methods.
A scoring function in macromolecular docking is solely based on empirical methods.
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Macromolecular representation involves the use of geometric descriptors to describe the shape of macromolecules.
Macromolecular representation involves the use of geometric descriptors to describe the shape of macromolecules.
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Semiflexible docking involves both interacting molecules being treated as fully flexible.
Semiflexible docking involves both interacting molecules being treated as fully flexible.
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Distance constraints in macromolecular docking can lead to an increase in the conformational search space.
Distance constraints in macromolecular docking can lead to an increase in the conformational search space.
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Scoring functions in macromolecular docking can include empirical and clustering-based methods.
Scoring functions in macromolecular docking can include empirical and clustering-based methods.
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Binding energy analysis only considers electrostatic interactions and ignores van der Waals forces.
Binding energy analysis only considers electrostatic interactions and ignores van der Waals forces.
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Clustering-based methods assume that the presence of numerous similar solutions indicates correctness.
Clustering-based methods assume that the presence of numerous similar solutions indicates correctness.
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Interface analysis focuses on the dynamics of protein chains rather than their structural conformations.
Interface analysis focuses on the dynamics of protein chains rather than their structural conformations.
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Hot spot residues do not play a significant role in the binding free energy of macromolecular complexes.
Hot spot residues do not play a significant role in the binding free energy of macromolecular complexes.
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FastContact is designed to assess the interaction between proteins and nucleic acids exclusively.
FastContact is designed to assess the interaction between proteins and nucleic acids exclusively.
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The two-stage ranking approach in scoring functions uses a fast-to-compute function followed by a more accurate function.
The two-stage ranking approach in scoring functions uses a fast-to-compute function followed by a more accurate function.
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The contributions of individual residues to binding energy are highlighted through methods like alanine scanning mutagenesis.
The contributions of individual residues to binding energy are highlighted through methods like alanine scanning mutagenesis.
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The biological unit of a protein is also referred to as the functional unit.
The biological unit of a protein is also referred to as the functional unit.
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Zinc is not necessary for the stabilization of zinc finger motifs in DNA binding proteins.
Zinc is not necessary for the stabilization of zinc finger motifs in DNA binding proteins.
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Amyloid β has solely pathological functions related to Alzheimer's disease.
Amyloid β has solely pathological functions related to Alzheimer's disease.
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Electrostatic interactions between positive side chains and the negative backbone of nucleic acids play a role in protein-nucleic acid interactions.
Electrostatic interactions between positive side chains and the negative backbone of nucleic acids play a role in protein-nucleic acid interactions.
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Crystal contacts during protein crystallization can simplify the identification of native quaternary structure.
Crystal contacts during protein crystallization can simplify the identification of native quaternary structure.
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Helix-turn-helix motifs typically involve recognition of the minor groove of DNA.
Helix-turn-helix motifs typically involve recognition of the minor groove of DNA.
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The concept of artifacts in crystallization refers to concerns about the conformation of specific surface regions.
The concept of artifacts in crystallization refers to concerns about the conformation of specific surface regions.
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The RRM domain is associated with sequence-specific recognition of double-stranded DNA.
The RRM domain is associated with sequence-specific recognition of double-stranded DNA.
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The asymmetrical unit (ASU) in crystallography represents the simplest form of a protein structure to create the entire crystal.
The asymmetrical unit (ASU) in crystallography represents the simplest form of a protein structure to create the entire crystal.
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PDB databases exclusively contain structures of proteins that are in their quaternary state.
PDB databases exclusively contain structures of proteins that are in their quaternary state.
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Most proteins in the PDB have three or more crystal contacts that sum up to 40% of the protein solvent accessible surface area.
Most proteins in the PDB have three or more crystal contacts that sum up to 40% of the protein solvent accessible surface area.
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Experimental knowledge of oligomeric state is essential for correctly identifying the structure of the native complex.
Experimental knowledge of oligomeric state is essential for correctly identifying the structure of the native complex.
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REMARK 350 in headers of PDB files exclusively provides details about crystallization conditions.
REMARK 350 in headers of PDB files exclusively provides details about crystallization conditions.
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Predictive tools can sometimes substitute for experimental methods when determining macromolecular complex structures.
Predictive tools can sometimes substitute for experimental methods when determining macromolecular complex structures.
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It is always guaranteed that the author-proposed biological unit in PDB entries is correct.
It is always guaranteed that the author-proposed biological unit in PDB entries is correct.
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Obligate protein complexes can function independently when isolated from their subunits.
Obligate protein complexes can function independently when isolated from their subunits.
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Approximately 75% of proteins in a cell exist solely as monomers.
Approximately 75% of proteins in a cell exist solely as monomers.
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Non-obligate complexes are capable of existing and functioning independently as single polypeptides.
Non-obligate complexes are capable of existing and functioning independently as single polypeptides.
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Oligomerization of proteins is largely disfavored by evolutionary processes.
Oligomerization of proteins is largely disfavored by evolutionary processes.
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Mutual interaction between protomers in oligomeric proteins is primarily due to favorable interface characteristics.
Mutual interaction between protomers in oligomeric proteins is primarily due to favorable interface characteristics.
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The primary role of oligomerization is to limit the structural complexity of proteins.
The primary role of oligomerization is to limit the structural complexity of proteins.
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Cooperativity in proteins can stem from oligomerization, enhancing biological activity through allostery.
Cooperativity in proteins can stem from oligomerization, enhancing biological activity through allostery.
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Proteins subunits in obligate complexes retain their activity when isolated from the complex.
Proteins subunits in obligate complexes retain their activity when isolated from the complex.
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All three approaches for the definition of interfaces provide identical results in interface analysis.
All three approaches for the definition of interfaces provide identical results in interface analysis.
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PDBsum provides schematic diagrams for both protein-protein interactions and protein-nucleic acid interactions.
PDBsum provides schematic diagrams for both protein-protein interactions and protein-nucleic acid interactions.
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Knowledge of hot spots in macromolecular interactions is crucial for drug design and understanding binding processes.
Knowledge of hot spots in macromolecular interactions is crucial for drug design and understanding binding processes.
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The size of hot spots in protein complexes is primarily determined by their solvent accessibility rather than their contribution to binding free energy.
The size of hot spots in protein complexes is primarily determined by their solvent accessibility rather than their contribution to binding free energy.
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Voronoi diagrams are exclusively used for studying protein-nucleic acid interactions.
Voronoi diagrams are exclusively used for studying protein-nucleic acid interactions.
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The PISA tool is designed solely for the analysis of protein-nucleic acid interfaces.
The PISA tool is designed solely for the analysis of protein-nucleic acid interfaces.
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Methods based on the change in solvent accessible surface area are among the most established approaches for interface analysis.
Methods based on the change in solvent accessible surface area are among the most established approaches for interface analysis.
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Mutations that are classified as hot spots generally reduce the binding free energy of the complex.
Mutations that are classified as hot spots generally reduce the binding free energy of the complex.
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Prediction of mutation impact on protein function relies only on empirical data.
Prediction of mutation impact on protein function relies only on empirical data.
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Rational design of proteins can involve modifying properties like stability, function, and solubility.
Rational design of proteins can involve modifying properties like stability, function, and solubility.
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RosettaDesign uses a fixed sequence of trials to determine the structure of mutant proteins.
RosettaDesign uses a fixed sequence of trials to determine the structure of mutant proteins.
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Aggrescan3D and SoluProt are tools specifically aimed at predicting protein folding.
Aggrescan3D and SoluProt are tools specifically aimed at predicting protein folding.
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Empirical scoring functions play a role in predicting stability changes upon mutation.
Empirical scoring functions play a role in predicting stability changes upon mutation.
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Machine learning methods in protein engineering are used purely for structural analysis.
Machine learning methods in protein engineering are used purely for structural analysis.
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The introduction of mutations can only decrease a protein's solubility.
The introduction of mutations can only decrease a protein's solubility.
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Missense mutations can enhance protein folding and increase stability.
Missense mutations can enhance protein folding and increase stability.
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Energy-based tools like Rosetta-ddG focus on structural features without considering energy metrics.
Energy-based tools like Rosetta-ddG focus on structural features without considering energy metrics.
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Aggregation-prone regions typically consist of sequences of 5-15 hydrophobic residues.
Aggregation-prone regions typically consist of sequences of 5-15 hydrophobic residues.
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The prediction of pathogenicity focuses solely on qualitative results.
The prediction of pathogenicity focuses solely on qualitative results.
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Hybrid approaches such as PROSS integrate both empirical and evolutionary-based methodologies.
Hybrid approaches such as PROSS integrate both empirical and evolutionary-based methodologies.
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Introducing a hydrophilic residue into the protein core can potentially increase solubility.
Introducing a hydrophilic residue into the protein core can potentially increase solubility.
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The introduction of mutations affecting protein dynamics can improve the adaptability of rigid protein regions.
The introduction of mutations affecting protein dynamics can improve the adaptability of rigid protein regions.
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The loss of interactions with inhibitors is a primary characteristic of HIV-1 protease mutants, leading to drug resistance.
The loss of interactions with inhibitors is a primary characteristic of HIV-1 protease mutants, leading to drug resistance.
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Mutations can only disrupt the transport of specific molecules and cannot allow the transport of different molecules.
Mutations can only disrupt the transport of specific molecules and cannot allow the transport of different molecules.
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Increased aggregation of proteins is typically associated with a high level of α-structures.
Increased aggregation of proteins is typically associated with a high level of α-structures.
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Changes in charge and hydrophobicity primarily affect the protein's binding and catalysis functionalities.
Changes in charge and hydrophobicity primarily affect the protein's binding and catalysis functionalities.
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Missense mutations can result in modifications that only impact protein localization without affecting folding.
Missense mutations can result in modifications that only impact protein localization without affecting folding.
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Glycine is recognized as the most rigid amino acid due to its unique conformation.
Glycine is recognized as the most rigid amino acid due to its unique conformation.
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Hot spots are generally found in loosely packed regions at the center of the interface.
Hot spots are generally found in loosely packed regions at the center of the interface.
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Knowledge-based methods for predicting hot spots use evolutionary conservation as one of their features.
Knowledge-based methods for predicting hot spots use evolutionary conservation as one of their features.
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Silent mutations always result in a change in the protein sequence.
Silent mutations always result in a change in the protein sequence.
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Energy-based methods predict hot spots by calculating the change in binding free energy upon in silico modification of a residue.
Energy-based methods predict hot spots by calculating the change in binding free energy upon in silico modification of a residue.
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Missense mutations introduce a stop codon that leads to protein truncation.
Missense mutations introduce a stop codon that leads to protein truncation.
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The introduction of insertions or deletions can lead to frameshift mutations due to changes in codon grouping.
The introduction of insertions or deletions can lead to frameshift mutations due to changes in codon grouping.
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The Human Genome Variation Society provides a comprehensive list of mutation databases sorted by types.
The Human Genome Variation Society provides a comprehensive list of mutation databases sorted by types.
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UniProtKB/Swiss-Prot consists of low-quality protein entries with limited known sequence variants.
UniProtKB/Swiss-Prot consists of low-quality protein entries with limited known sequence variants.
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The calculation of solvent accessible surface area (ASA) is used to effectively predict binding sites in macromolecular analysis.
The calculation of solvent accessible surface area (ASA) is used to effectively predict binding sites in macromolecular analysis.
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A mutation introducing a charged residue in a neutral environment is likely to destabilize the protein.
A mutation introducing a charged residue in a neutral environment is likely to destabilize the protein.
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Study Notes
Macromolecular Complexes and Interactions
- Macromolecular complexes involve two or more polypeptide chains (protomers) associating to form an oligomer.
- Protein-protein and protein-nucleic acid interactions are crucial for all cellular processes, including metabolism, transport, signal transduction, genetic activity (transcription, translation, replication, repair), membrane trafficking, and mobility.
Protein-Protein Complexes
-
Obligate complexes: Protomers (individual polypeptides) cannot function independently, but only when associated.
- Examples include GABA receptors, ATP synthase, many ion channels, and ribosomes.
-
Non-obligate complexes: Protomers can exist and function independently.
- Examples include hemoglobin, beta-2 adrenergic receptor, and insulin receptor.
Protein Oligomerization
- Oligomerization is a common feature of proteins.
- Approximately 75% of proteins in a cell are oligomers.
- Homo-oligomers are the most frequent type.
- Some proteins exist exclusively as oligomers.
- Oligomerization interfaces are often symmetric and complementary.
- Oligomerization is favored by evolution.
Advantages of Oligomerization
- Morphology: More complex structures are often required for multiple functions (e.g., membrane pores).
- Cooperativity: Allostery (modulation of biological activity) and multivalent binding.
- Stability against denaturation: Smaller surface area.
- Redundancy and error control: For example, in protein translation control.
Oligomerization Interface Characteristics
- Large surface area—greater than 1400 Ų.
- Tendency to circular or planar shape (not always for obligate complexes).
- Surface residues often protrude.
- Non-polar residues substantially outnumber polar residues (approximately 2/3 versus 1/5) compared to other protein surface regions.
- Hot-spot residues: Primarily responsible for oligomeric interactions; more evolutionarily conserved and typically polar located towards the center of the interface.
Oligomerization vs. Aggregation
- Oligomers are soluble, have a precise native fold, and are often reversible.
- Aggregates are insoluble, can be heterogeneous, involve denatured proteins, and are irreversible.
- The function of certain proteins involves aggregation.
- Aggregates are not always pathological.
Non-pathological Aggregates
- Keratin filaments (e.g., in hair, skin, and nails).
- HET-S (in fungal reproduction and apoptosis).
Pathological Aggregates
- Amyloid β from the human brain (involved in Alzheimer's disease) exhibits different morphologies (I and II) and a transition from I to II.
Non-pathological Functions of Amyloid β
- Blood-brain barrier maintenance.
- Anti-microbial peptide function.
- Synapse function.
Protein-Nucleic Acid Interactions
- Non-specific: Electrostatic interactions with negative charges on the nucleic acid backbone (lysine and arginine residues).
- Specific: Recognition of particular nucleotide sequences involving major groove (B-DNA), minor groove (A-DNA or A-RNA), and single-stranded RNA.
DNA Binding Proteins
- Helix-turn-helix: (+)-sidechains, perpendicular helices, recognition of major groove.
- Zinc finger: Stabilized by zinc ions (Zn²⁺) bound to cysteine and histidine residues; important for folding and mediating DNA binding.
RNA Binding Proteins
- RRM (RNA recognition motif): βαββαβ barrel-like arrangement, sequence-specific RNA recognition.
- KH domain: ssRNA/DNA binding via hydrogen bonds, electrostatic and shape complementarity.
- PUF domain: Each helix recognizes a single base.
Quaternary Structure in PDB Database
- Asymmetric unit (ASU): Macromolecular structures from X-ray crystallography; the smallest portion of a crystal structure.
- Unit cell or crystal unit: The basic unit of a crystal that is repeated in three dimensions to generate the entire crystal.
- Crystal contacts: Intermolecular contacts caused by protein crystallization; can interfere with the identification of the native quaternary structure of the protein.
- Artifacts of crystallization: Concerns about conformation in some surface regions due to crystallization; can affect loops or side chains and complicate mutation analysis.
Biological vs. Asymmetric Unit
- A biological unit can comprise multiple copies, one copy, or part of the asymmetric unit.
Complex or Artifact?
- Many proteins in the PDB have multiple crystal contacts that represent a significant portion of the protein's surface area.
- Determining biologically relevant contacts from crystal contacts is a challenge.
- Experimental knowledge of an oligomeric state assists in identifying the structure of the native complex.
Prediction of 3D Structure of Complexes
-
Homology-based predictions: Build a complex based on a similar complex with a known structure, assuming interaction information is transferable.
- Close homologs (≥40% sequence identity) are more likely to interact similarly.
- Sequence similarity doesn't always imply similarity in interactions.
- Machine learning-based predictions.
- Macromolecular docking: Predicting the optimal configuration of two or more macromolecules.
- Various docking methods exist, ranging from simple rigid-body docking to more sophisticated methods that account for flexibility in side chains using predefined rotamer libraries.
Macromolecule representation methods
- Geometric descriptors: Use shapes (spheres), normals, and vectors from molecule center.
- Discretization of space: Employing grid representation as a way to represent the spatial conformation of molecular structures.
- Fully rigid approximation
- Soft docking
- Explicit side-chain flexibility
- Docking to a molecular ensemble. This method requires docking multiple crystal structures from NMR analysis or MD simulation.
- Rigid body docking
Macromolecular Docking - Search and scoring
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Search Methods
- Exhaustive search: Full conformational space exploration to determine every possible relative configuration. (Difficult and computationally expensive).
- Stochastic methods: Random search methods (Monte Carlo, genetic algorithms, Brownian dynamics) used to reduce computational costs compared to exhaustive search.
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Scoring methods
- Two-stage ranking: An approximate, quick function is used to eliminate unlikely solutions. A second, more precise function is used to select optimal solutions.
- Empirical, knowledge-based, force-field-based, and clustering-based scoring: Different scoring function types that address various aspects of the interactions.
Analysis of Macromolecular complexes
- Binding energy: Evaluation of energetic components of protein-protein interactions, such as electrostatic, van der Waals, and desolvation. Tools like FastContact can help rapidly compute binding energy. The results highlight hotspot interactions.
- Macromolecular interface: The area where two protein chains or protein and nucleic acid chains interact.
- Interface analysis: The process of identifying interface residues and the interactions that are essential for stability and activity. Includes methods based on distance, solvent accessible surface area, and computational geometry. databases, and tools.
- Interaction hotspots: Residues critically involved in binding, usually highly conserved. The location and characteristics of hotspots can be useful in understanding molecular recognition principles.
Engineering of Protein Structures
- Protein engineering: Modifying protein structures through mutagenesis. Useful for optimization
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Properties that can be modified
- Stability
- Function (e.g., binding site, catalytic activity, substrate specificity)
- Macromolecular interface
- Molecular tunnels/channels
- Solubility
Prediction of Stability Changes upon Mutation
- Empirical scoring functions: Methods developed from experimental data.
- Evolutionary conservation analysis (back-to-consensus): Based on comparing the conserved amino acid types across related proteins/sequences.
- Machine learning approaches: Artificial intelligence for prediction via trained datasets.
Rational Design: Function
- RosettaDesign: A tool for predicting minimum-energy mutant structures using Monte Carlo.
- Free energy changes: Helps in designing mutations to optimize binding sites.
Rational Design: Solubility
- Aggrescan3D/SoluProt: Tools for identifying stabilizing mutations to reduce aggregation tendency.
- Solubis: Tool for identifying stabilizing mutations to reduce aggregation tendency.
Prediction of Pathogenicity
- Machine learning approaches: Used to find predictions from data.
- Qualitative results: Identifying deleterious versus neutral mutations.
Identification of Mutable Residues
- Evolutionary conserved residues: Tend to be critical for stability/function and mutations have more significant consequences.
- Highly variable residues: Mutations often have neutral effects.
- Mutation effects on stability & folding: Impact mutations in critical areas such as protein core, surface residues, and polar/hydrophobic changes as determined by the interaction hotspot predictions.
- Mutation effects on function: Mutation effects on binding sites, transport pathways, flexibility, and protein localization.
Prediction of Effects on Structure
- Workflow: Identifying the mutated residue and its surroundings, selecting suitable rotamers from a library of structures, and optimizing to achieve a stable low-energy structure.
- Tools: Geometric tools (e.g., PyMOL, WhatIF), energy-based tools (e.g., FOLDX, Rosetta), and homology-based tools (e.g., Swiss Model, MODELLER).
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Test your knowledge on protein oligomerization and interface analysis with this specialized quiz. Explore concepts such as 'hot-spot' residues, reversible oligomers, and tools like PISA and PDBsum. Perfect for students and professionals in biochemistry and molecular biology.
