Molecular Evolution and Protein Structure

Podcast

Play an AI-generated podcast conversation about this lesson

Questions and Answers

Which of the following protein properties can be predicted from its primary sequence?

Post-translational modifications

Enzymatic activity

Transmembrane regions (correct)

Tertiary structure

How do alignment models infer evolutionary relationships among proteins?

By analyzing their functional groups

By focusing solely on the protein's tertiary structure

By measuring their molecular weights

By assessing their sequence similarities (correct)

What is a critical requirement for variations to be passed on to subsequent generations in evolutionary processes?

The variations should occur in only a few individuals

The variations must be acquired during the individual's lifetime

The variations must be large and noticeable

The variations need to be heritable (correct)

Which concept serves as a fundamental aspect of how proteins adapt to their environments?

Natural selection of fitness-increasing variations Signup and view all the answers

What factor significantly enhances the accuracy of predictions made by methods analyzing protein sequences?

Inclusion of evolutionary information Signup and view all the answers

In the context of molecular evolution, what primarily drives changes in protein function?

Improved functions in a given environment (adaptation) Signup and view all the answers

Which of the following statements about evolutionary pressure is accurate?

It selects for traits that improve adaptability and function. Signup and view all the answers

Why is protein sequence alignment significant in the study of evolution?

It helps infer homology based on evolutionary relationships. Signup and view all the answers

What is the primary disadvantage of the mmCIF format?

It is difficult to read. Signup and view all the answers

Why are large systems like ribosomal subunits broken down into multiple PDB files?

To simplify analysis of individual components. Signup and view all the answers

What advantage does the mmCIF format provide over traditional PDB files?

It allows detailed linking of associated fields. Signup and view all the answers

Which step in protein synthesis involves converting mRNA into protein?

Translation Signup and view all the answers

What is a drawback of using mmCIF files when accessing individual entries?

They contain too much information. Signup and view all the answers

Which sequence information paradigm describes the relationship among sequence, structure, and function?

Sequence-structure-function paradigm Signup and view all the answers

Which of the following is a primary advantage of using the mmCIF format for data consistency?

Explicit tagging of information fields. Signup and view all the answers

What is the correct sequence of protein synthesis steps?

Transcription, Translation, Post-translational modifications. Signup and view all the answers

What happens if a wrong template is chosen during homology modelling?

The final structure will have inaccuracies. Signup and view all the answers

Which factor is NOT important when selecting a template for homology modelling?

The number of amino acids in the template. Signup and view all the answers

Why is the quality of sequence alignment important in homology modelling?

It directly affects the accuracy of the final model. Signup and view all the answers

What is one possible outcome of using multiple templates in homology modelling?

Creation of a combined model. Signup and view all the answers

What is a common issue with pairwise target-template alignments?

They often contain errors. Signup and view all the answers

Which method is NOT mentioned as a sophisticated approach for improving alignments?

Randomized sequence modeling. Signup and view all the answers

Which criterion can be used to assess template selection aside from sequence identity?

Resolution of the template structure. Signup and view all the answers

What decreases the reliability of sequence alignment in homology modelling?

Decreased similarity between target and template. Signup and view all the answers

What does a B-factor represent in X-ray crystallography?

The measure of atom oscillation around specified positions Signup and view all the answers

What is a significant disadvantage of X-ray crystallography?

It requires a non-native crystalline state for analysis Signup and view all the answers

Which method allows for the detection of hydrogen positions in macromolecules?

NMR spectroscopy Signup and view all the answers

What does the RMSD parameter indicate in NMR structure determination?

Differences between individual conformations of the molecule Signup and view all the answers

Which statement best describes a characteristic of electron microscopy?

It can be applied to extremely large systems. Signup and view all the answers

What is a key limitation of NMR spectroscopy when analyzing larger proteins?

It is limited to proteins approximately 40 kDa in size. Signup and view all the answers

How does the atomic resolution of X-ray crystallography compare to other methods?

It is generally higher than that achieved by electron microscopy. Signup and view all the answers

Which aspect is NOT an advantage of NMR spectroscopy?

Applicability to large crystalline structures Signup and view all the answers

What is the purpose of template selection in homology modelling?

To identify a suitable sequence alignment for the target Signup and view all the answers

Which of the following steps comes directly after template selection in homology modelling?

Sequence alignment Signup and view all the answers

In the context of homology modelling, what does loop and side-chain modeling primarily focus on?

Refining the flexible regions of the protein structure Signup and view all the answers

What does optimization in homology modelling aim to improve?

The quality and stability of the final protein model Signup and view all the answers

Which process occurs first in homology modelling?

Database search Signup and view all the answers

What is the first step in the pairwise energy-based methods for fold recognition?

Aligning the query sequence with each structural fold Signup and view all the answers

Which of the following statements accurately describes the process of building a crude model in fold recognition?

It replaces aligned residues in the template with query residues. Signup and view all the answers

In pairwise energy-based methods, what is typically the last step of the fold recognition?

Calculating the energy of the raw model Signup and view all the answers

What does the fold library provide during the fold recognition process?

A set of templates for structural alignment Signup and view all the answers

Which criterion is primarily used to determine the best matching structural fold in fold recognition?

Energy-based criteria Signup and view all the answers

Study Notes

Course Information

Examination format: written exam, multiple choice, 25 questions, 25 points
Exam dates:
- December 10/17, 2024 (voting required)
- January 2025
- February 2025
Failing grade: less than 10

Structure Visualization

Bonds-based representation:
- Fast, resource-efficient
- Suitable for detailed analysis
- Can give an inaccurate impression of atom packing and interatomic distances
- Hydrogen atoms often omitted for simplicity
Stick representation
- Visualizes molecular connections
- Suitable for detailed analysis
- Can give an inaccurate impression of atom packing and interatomic distances
- Hydrogen atoms often omitted for simplicity
Ball-and-stick representation:
- Shows atoms and bonds clearly
- Helps to identify essential features
- More resource-intensive
Color coding used to distinguish different atoms:
- Hydrogen (white)
- Carbon (black)
- Nitrogen (blue)
- Oxygen (red)
- Fluorine/Chlorine (green)
Backbone-based representation:
- Fairly fast, not heavily resource-intensive.
- Useful for analyzing secondary structures and protein folds
- Shows major landmarks
- Useful for overall structural orientation

Surface-based representation

CPK/spheres and surface:
- Very slow and resource-intensive
- Useful for studying shapes, volumes, cavities and molecular contacts

Energetics of Structures

Energy contains: internal energy (U) enthalpy (H) potential energy (E_p) kinetic energy (E_k)
Convention: negative energy is favorable (preferred). Positive energy is unfavorable (not preferred).
Entropy (S): related to thermal disorder or conformational availability (degrees of freedom). Higher entropy is more favorable (preferred). The total entropy (S) is always greater than 0
Free energy (G): a combination of internal energy and entropy; often expressed as ΔG; ΔG <0 is favorable. ΔG = ΔH - TΔS (at a constant temperature.)
Energy landscape: relationship between structure and its potential energy. Stable structures (Minima) Transient structures (Saddle points) Unstable structures (Maxima) Energy barriers Multidimensional surface

Molecular Interactions

Covalent interactions (chemical bonds):
- Between two atoms sharing electrons.
- Very stable.
Non-covalent interactions:
- Much weaker than covalent bonds.
  - Electrostatic interactions (Coulomb's Law).
  - Polar interactions (hydrogen bonds).
  - Non-polar interactions (vdW interactions).
  - Hydrophobic interactions
Electrostatic interactions (ionic interactions):
- Environment-dependent.
- Dependent on permittivity/dielectric constant (vacuum, air, protein, water, ...).
- Salt concentration and pH can affect electrostatic interactions.
Polar interactions:
- Often involve H-bonds.
- A bond involving a hydrogen atom between a highly electronegative atom.
- Aromatic (π-π) interactions:
- Attractive interaction between aromatic rings; the distance between the center of rings is ~5Å. Arrangements like parallel, T-shaped, sandwich.
- Van der Waals (vdW) interactions:
- Between any two atoms. Short-range (up to 5 Å) interactions.
- Hydrophobic interactions:
- Entropic origin. Driven by water molecules around hydrophobic moieties (unfavorable) allowing for a favorable release of ordered water molecules
Disulfide bonds (cysteine bridges):
- Formed via oxidation of cysteine residues
- Important for structural stability.
Cation-π interactions:
Electrostatic interaction of a positively charged residue with an aromatic residue.

Structure Determination

X-ray crystallography - advantages and disadvantages.
- Advantages:
  - No limitations in size.
  - Possibility to obtain atomic resolution.
- Disadvantages:
  - Requires a crystal.
  - Structure in crystalline state (not always native).
  - Static picture of macromolecule
  - Position of hydrogen atoms not always detected.
NMR Spectroscopy - advantages and disadvantages
- Advantages:
  - Structure in solution state (native).
  - Possibility to investigate dynamics of macromolecules.
  - Position of hydrogen atoms detected.
- Disadvantages:
  - Size limited. 40 kDa proteins (~ 400 amino acid proteins)
  - Requirement for isotopically labeling of samples
Electron microscopy - advantages and disadvantages:
- Advantages:
  - Applicable to very large molecules.
  - Complements X-ray and NMR.
- Disadvantages:
  - Lower resolution (2-3 Å).

Bioinformatics predictions

Homology Modeling -
Machine learning -
Ab initio prediction -
Comparative Modeling -
Steps:
- Find similar proteins.
- Align sequences.
- Build the framework of the model
- Add sidechains
- Refine model
Ab initio predictions - predicting structure without a template.
Advantages and disadvantages of these methods.

Biomolecules

Proteins:
- Primary structure: linear sequence of amino acids.
- Secondary structure: local 3D structures (α-helices, β-sheets, etc.).
- Tertiary structure: overall 3D structure of a polypeptide chain.
- Quaternary structure: arrangement of multiple polypeptide chains in a protein complex.
Nucleic acids:
- Structure:
- Primary structure: linear sequence of nucleotides.
- Secondary structure: base-pairing(e.g. Watson-Crick), motifs.
- Tertiary structure: 3D structures of DNA (e.g., B-DNA). Format and databases.

Protein structure

Hierarchy of protein structure (primary, secondary, tertiary, and quaternary).
20 amino acids (different classifications).
Primary structure (detailed discussion of the primary structure of the protein and different types of connections)
Different geometries of protein backbone (Φ, Ψ)
Different secondary structures (α-helices, β-sheets, loops and coils).
Tertiary structure- (discussion of the different components and processes in tertiary structure)
Quaternary structure- Discussion of the different proteins associated together.

Studying That Suits You

Use AI to generate personalized quizzes and flashcards to suit your learning preferences.

Description

This quiz explores key concepts related to molecular evolution and protein structure, including protein properties, evolutionary relationships, and the significance of protein sequence alignment. Test your understanding of how proteins adapt and the factors influencing predictions in evolutionary biology.