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Structural Bioinformatics and Protein Structure Prediction (1)

Structural bioinformatics focuses on analyzing and predicting the 3D structures of biological macromolecules, which is crucial for understanding their functions and applications in drug design and disease mechanisms. Protein structure prediction methods include homology modeling, ab initio modeling, and threading, each with specific techniques and tools. Future advancements in the field involve AI integration, personalized medicine, and addressing challenges in predicting complex structures.

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6 views

Structural Bioinformatics and Protein Structure Prediction (1)

Structural bioinformatics focuses on analyzing and predicting the 3D structures of biological macromolecules, which is crucial for understanding their functions and applications in drug design and disease mechanisms. Protein structure prediction methods include homology modeling, ab initio modeling, and threading, each with specific techniques and tools. Future advancements in the field involve AI integration, personalized medicine, and addressing challenges in predicting complex structures.

Uploaded by

amarsingham1357
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© © All Rights Reserved
Available Formats
Download as PDF, TXT or read online on Scribd
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Structural Bioinformatics and

Protein Structure Prediction

Instructor : Ajay Samuel.


Introduction to Structural Bioinformatics
• Definition: Structural bioinformatics is a subfield of bioinformatics
that focuses on the analysis and prediction of the three-dimensional
(3D) structure of biological macromolecules such as proteins, nucleic
acids, and complexes.
• Importance: Understanding the 3D structure of macromolecules is
crucial because the structure is directly related to their function.
Knowledge of these structures can aid in drug design, understanding
disease mechanisms, and developing new therapeutic strategies.
• Applications: Structural bioinformatics is applied in drug discovery
(designing molecules that can interact with specific protein targets),
understanding the molecular basis of diseases, and engineering
enzymes with new functions.
Importance of Protein Structure Prediction
• Motivation: Proteins perform a wide range of functions in biological
systems, and their functions are determined by their structures.
Accurate prediction of protein structures from sequences can help
understand how proteins work and how they interact with other
molecules.
• Challenges: Predicting protein structures is complex due to the vast
number of possible conformations a protein chain can adopt and the
intricate interactions that stabilize its structure.
• Impact: Predicting protein structures can lead to insights into
biological processes, the development of new drugs, and the creation
of synthetic proteins with novel functions.
Protein Structure Prediction Methods
Overview: There are three main methods for protein structure
prediction:
• Homology Modeling: Predicts the structure of a protein based on the
known structures of homologous proteins.
• Ab Initio Modeling: Predicts the structure from scratch, based only on
the protein sequence and physical principles.
• Threading (Fold Recognition): Identifies compatible folds from known
protein structures that may match the sequence of the target protein.
Homology Modeling
Concept:
Homology modeling relies on the observation that homologous
proteins (those with similar sequences) tend to have similar structures.
By aligning the sequence of an unknown structure to a known template,
a model can be generated.
Homology Modeling Steps:
Identify homologous sequences: Use sequence alignment tools to find
proteins with similar sequences.
Align target and template sequences: Create an alignment to match the
sequences.
Build model based on template structure: Use the alignment to
construct a model of the target protein.
Refine and validate model: Adjust the model to better fit known
physical and chemical constraints and validate its accuracy.
Tools: Common tools for homology modeling include MODELLER,
SWISS-MODEL, and Phyre2.
Ab Initio Modeling
Concept:
Ab initio modeling, also known as de novo modeling, attempts to predict protein structures
purely based on physical principles without using template structures.
Approaches:
• Energy minimization: Finds the structure that minimizes the potential energy of the protein.
• Molecular dynamics simulations: Uses simulations of physical movements to explore possible
conformations.
• Fragment assembly: Builds the structure from small fragments that have known conformations.

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.

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