Structural Bioinformatics and Protein Structure Prediction (1)
Structural Bioinformatics and Protein Structure Prediction (1)
Tools: Tools for ab initio modeling include Rosetta, QUARK, and AlphaFold.
Structure-Based Drug Design
Definition: Structure-based drug design (SBDD) is the process of designing new
drugs based on the 3D structure of target proteins.
Steps:
• Target identification and validation: Identify and validate the biological target
(protein) for the drug.
• Hit identification (virtual screening): Use computational methods to screen
large libraries of compounds for those that are likely to bind to the target
protein.
• Lead optimization: Refine the hits to improve their binding affinity, specificity,
and other pharmacological properties.
Example: The development of HIV protease inhibitors, which block the activity
of the viral protease enzyme, is a successful example of structure-based drug
design.
Software Tools for Protein Structure Prediction
MODELLER:
• Description: An automated tool for homology modeling that generates 3D
structures of proteins based on a given alignment with known structures.
• Features: Includes sequence alignment, model building, and refinement
capabilities.
• Usage: Suitable for homology-based predictions and comparative modeling.
Rosetta:
• Description: A comprehensive suite of tools for protein structure prediction,
design, and docking.
• Features: Capabilities include ab initio prediction, protein folding, protein
design, and ligand docking.
• Usage: Widely used for ab initio modeling and protein design projects.
Software Tools for Protein Structure Prediction
Other Tools:
SWISS-MODEL: A web-based tool for automated homology modeling.
Phyre2: A web-based service for protein structure prediction using
homology and threading methods.
AlphaFold: An AI-based tool for accurate protein structure prediction.
MODELLER
Overview: MODELLER is a widely used tool for comparative or homology
modeling of protein structures.
Capabilities:
• Sequence alignment: Align target sequences with known template structures.
• Model generation: Create 3D models based on the alignment.
• Refinement: Optimize the generated model to better fit physical and chemical
constraints.
Workflow:
• Input: Provide the sequence of the target protein and the structure of a
template protein.
• Process: Use MODELLER to align the sequences, generate a model, and refine
it.
• Output: Obtain a predicted 3D structure of the target protein.
Rosetta
Overview: Rosetta is a versatile suite of tools used for various tasks in protein
structure prediction and design.
Capabilities:
• Ab initio prediction: Predict protein structures from sequences without
templates.
• Protein design: Design new proteins with desired functions or properties.
• Ligand docking: Predict how small molecules bind to proteins.
Workflow:
• Input: Provide the protein sequence or structural information.
• Process: Use Rosetta's algorithms for fragment assembly, energy minimization,
or design tasks.
• Output: Obtain predicted structures, designed proteins, or docked complexes.
Future Directions
Advancements:
• AI and Machine Learning: Use of advanced AI models like AlphaFold
for highly accurate structure prediction.
• Integration with Experimental Data: Combining computational
predictions with experimental techniques like cryo-EM and NMR for
enhanced accuracy.
Challenges:
• Complex Structures: Predicting structures of large protein complexes
and membrane proteins.
• Dynamic Information: Incorporating protein dynamics and
conformational changes into predictions.
Future Directions
• Opportunities:
• Personalized Medicine: Tailoring treatments based on individual
protein structures.
• Novel Drug Discovery: Discovering new drugs using predicted
structures.
• Understanding Complex Diseases: Using structural insights to
understand the molecular basis of diseases.